Set in Academy City, a city of scientifically advanced superhuman students, located to the west of Tokyo, in a world where magic is also real. Kamijou Touma's right hand, the Imagine Breaker, can negate all magic, psychic, or divine powers, but not his own bad luck. One day he finds a young girl, Index, hanging on his balcony railing. She turns out to be a nun from the Church of England, and her mind has been implanted with the Index Librorum Prohibitorum — all the magical texts the Church has removed from circulation. His encounter leads him to meet others from the secret world of science and magic and right into an adventure where science and magic collide.
Following the fake boyfriend incident with Mikoto, Tōma still hasn't finished his summer homework and Index isn't helping much. Whilst Tōma takes Index to a restaurant for a change of location, they are attacked by magician named Ouma Yamisaka who kidnaps Index and runs off. As Tōma tries to find her, running into Mikoto along the way, Ouma prepares a ceremony that will allow him to access the grimoires inside Index's head in order to find a cure for a curse inflicted on a woman he has fallen in love with. As the ceremony begins, Ouma's body and mind is put through excruciating pain trying to access the grimoires. Thanks to Index using her new cellphone, Tōma is able to find her and stop the ceremony. Tōma gets Ouma to snap out his pitiful state and offers to cure the woman's curse using his Imagine Breaker. Meanwhile, Kanzaki is seen fighting the Knights of England.
Archbishop Laura informs Stiyl that the Liber AL vel Legis has been stolen by the Amakusa Catholics and sends him to Japan along with a group of Catholic battle nuns known as the Agnese Forces, to search for the grimoire and Orsola Aquinas, the only one who can decode it who was also kidnapped by the Amakusas. In order to get Tōma's assistance, Stiyl pretends to kidnap Index. While Tōma coincidentally runs into Orsola on the way to save Index, the Amakusas appear and abduct her via a hole in the ground. After determining that the Amakusa's goal is to use a special teleport magic to escape with Orsola before midnight, Tōma, Index, Stiyl and the Agnese Forces set up camp at the required location, where Tōma gets into a lot of awkward situations with the group's leader, Agnese Sanctis. Because Kaori was once an Amakusa Catholic, Stiyl knows he may have to fight her if necessary. Meanwhile, the Amakusas prepare to make their move.
The Agnese Forces face off against the Amakusas as a diversion while Tōma, Stiyl and Index sneak inside the amusement park. While escaping from some Amakusa warriors, Tōma manages to find Orsola and gives her a crucifix that Styil gave him earlier. The two are reunited with Stiyl and Index, who are facing against the leader of the Amakusas, Saiji Tatemiya. Working together, Tōma and Stiyl defeat Saiji and the rest of the Amakusas are captured by Agnese's battle nuns. However, the captured Saiji reveals to Tōma and Index that the Amakusas have never stolen the Liber AL vel Legis, as the real reason the Catholic Church wanted Orsola was to kill her to prevent the secrets of the grimoire from being abused. The Amakusas only got involved as Orsola sought them for protection but ran away as she didn't trust them. Troubled by this revelation, Tōma asks two of the Battle Nuns, Luccia and Angelene to see Orsola again but he accidentally angers Luccia who tries to kill him, Index and Saiji. However, she and Angelene are forced to retreat when Index uses spell interception on Angelene's magic and counters Luccia's attack.
Stiyl explains that the Catholics won't kill Orsola until they can prove her to be a heretic. As Saiji leaves to free his comrades, Stiyl tells Tōma and Index to go home, since they have no further stake in this matter. Tōma, however, goes by himself to where Orsola is being held and tortured by Agnese's battle nuns, who reveal they deceived Necessarius to assist them. He is later joined by Stiyl, who reveals the crucifix Tōma gave to Orsola means she is under protection of the Church of England, followed by Index and the Amasukas. Whilst Tōma is put in charge in protecting Orsola, the others fend off the battle nuns, with Index utilizing the power "Sheol Fear", to deafen and paralyze some of the battle nuns. However, Luccia brings another force of battle nuns who willingly stab their ears to protect themselves from Sheol Fear.
As Tōma, Index, Stiyl, Saiji and Orsola barricade themselves from the battle nuns, Tōma and Index come up with an idea that Orsola could help them decipher the Liber AL vel Legis in Index's head to their advantage. When Orsola mentions her deciphering method, Index reveals her translations is a fake, revealing Orsola was never able to really decode the grimoire all along. Whilst the others fend off against the battle nuns, Tōma confronts Agnese who attacks him with her Lotus Wand. However, Tōma manages to learn its attack patterns and land a hit on Agnese. As Agnese tries to bluff that Tōma sacrificed his friends as decoys, they arrive with Innocentius, who Stiyl managed to summon thanks to the Amasukas. Her confidence broken, Agnese is knocked out by Tōma, breaking the battle nuns morale, before Tōma himself falls unconscious. Waking up in a hospital in Academy City, Tōma is greeted and taken care by Kaori, who thanks him for helping and tells him that Orsola and the Amasukas are now under the protection of the Church of England. Meanwhile, back in London, Laura reveals to Stiyl that the true reason she got involved with the Orsola incident was to get the Amakusa Catholics under her control and use them as leverage to ensure Kaori's loyalty to Necessarius.
Kuroko's day of shopping with Mikoto is interrupted by reports of robbers stealing an aerospace carrycase. Kuroko subdues the thieves but is then attacked and wounded by their leader, another teleporter named Awaki Musujime. She reveals to Kuroko about Tree Diagram's destruction and how various factions are gathering of its remnants, the contents of the carrycase being one of them. Kuroko manages to escape, but becomes concerned over what Awaki had told her, particularly concerning how Mikoto had been trying to stop them for reasons she had kept from her, (namely being that if Tree Diagram were rebuilt, the Level 6 Shift experiment would start over again). As Mikoto goes out that night to confront Awaki, Kuroko decides to follow her and overhears their conversation before Awaki escapes. As Kuroko decides to take matters into her own hands, Misaka 10032 decides to take action.
Kuroko finds Awaki at a nearby building and uses the latter's trauma of self-teleportion to make the first strike but during their battle, her injuries make her unable to concentrate on teleporting and she is trapped under a pile of furniture. Awaki explains to Kuroko that she and her organization, the Science Syndicate, plan to build a new Tree Diagram in order to create other species of espers. Awaki tries to persuade Kuroko to join her, believing her powers is a curse that caused her to become how she is. Kuroko rejects her offer, verbally abuses Awaki for making excuses for her own behavior, breaks loose and tries to attack Awaki, but is shot by her. After a brief traumatic loss of control over her powers, Awaki attempts to kill Kuroko by dropping the building on top of her, but she is saved by Mikoto and Tōma, who came to rescue her after he was alerted by Misaka 10032. As the Anti-Skill's stop the Science Syndicate, Awaki tries to escape but to her horror, is confronted by Accelerator who, using the Misaka Network to utilize his powers, defeats her and destroys the Tree Diagram remnant. As everyone recovers, Mikoto gives her thanks to Kuroko.
Academy City is hosting the Grand Champion Star Festival, a sports competition between the various schools of the city, during which visitors from outside the city are allowed entry. Whilst Tōma's parents, Tōya and Shiina, as well as Misuzu, a relative of Mikoto's, get to know each other, Tōma and Mikoto decide to make a bet in which the loser does anything the winner wants. Meanwhile, Laura contacts Aleister to inform him that magicians have infiltrated Academy City in order to make a transaction with a magical weapon called the Stab Sword, which has the power to kill a Saint. Meanwhile, Tōma has several troubles with a hungry Index and awkward situations with the class representative, Seiri Fukiyose. Later, Tōma runs into Stiyl and Tsuchimikado, who tell him about the intruding magicians and asks him not to get Index involved. Whilst getting scolded by Seiri after an awkward incident with Index and Komoe, Tōma runs into a woman named Oriana Thomson. When his Imagine Breaker reacts to her, he realizes she is one of the magicians in question and starts to follow her.
As Oriana realizes she's being followed and runs away, Tōma, Stiyl and Tsuchimikado chase her through a bus station filled with booby traps, but she manages to escape and uses a counter magic called Short Hand to avoid being traced. Despite Tōma's objections, Tsuchimikado and Stiyl undergo a painful magical spell in order to locate the Short Hand spell, which happens to be right in the center of a middle school ball throwing tournament. With the competitors in danger of being hurt by the spell if they touch it, Tōma and Tsuchimikado infiltrate the match as contestants in order to find it, only to find the opposing team is Mikoto's school. Tōma tries to protect Mikoto from one of the basket poles which he believes has the Short Hand, only for Seiri to end up touching the real one and gets hit by magic and falls unconscious before Tōma destroys the spell. As Seiri is taken to the hospital, Tōma vows to make Oriana pay on what she did.
Whilst Heaven Canceler attends to Seiri, Stiyl manages to lead Tōma and Tsuchimikado to Oriana's location. Oriana inflicts a curse on Tsuchimikado and gives Tōma trouble with her variety of spells, yet Tōma's determination allows him to land a hit on her. Oriana escapes but leaves behind her cargo, which is later revealed to be a decoy. Laura soon learns that the Stab Sword is actually St. Peter's Cross, which she fears the Catholic Church will use to put Academy City under their control if the trade goes through. After Tōma, Stiyl and Tsuchimikado are informed of this, Tōma has lunch with Index, his parents, Mikoto and Misuzu, and is surprise to learn Misuzu is Mikoto's mother.
After Tōma has some women trouble with Index, Mikoto and Kuroko following lunch, Tsuchimikado manages to find Oriana's location and instructs him and Stiyl to go there. However, whilst Tsuchikimado tries to track Oriana, she goes straight to him and attacks him. She defeats Tsuchikimado and destroys his search spell, but he manages to pull off a bluff that he has summoned reinforcements to trick her into running away before finishing him off. Meanwhile, Aisa becomes worried about Tōma, with Komoe suggesting she should invite him to a night parade at the end of the festival. However, when they bump into Oriana as she makes her escape, she sees Aisa's magic Celtic Cross and mistakes her for a Necessarius magician, attacking her with a vicious spell which leaves her brutally wounded. As Tōma falls into despair upon witnessing her state, Komoe recalls the healing spell she performed on Index, so Stiyl stays to help her perform it whilst Tōma chases after Oriana.
Tōma hears more from Tsuchimikado about the Croce di Pietro, which uses a similar type of magic to what Misha used, and have Orsola look further into it. Meanwhile, Stiyl manages to successfully heal Aisa, and later, Komoe is questioned by Tōma's parents about him. Tōma, Stiyl and Tsuchimikado head towards the meetup point of the trade, where they once again face against Oriana and find themselves at a disadvantage.
As Oriana and Tōma continue to battle, Stiyl recovers and summons Innocentius to help him. Refusing to give up, Oriana uses her full powers to defeat Stiyl and all of her spells on Tōma. As he is about to lose conscious, Tōma remember his promises to his friends and recuperate himself to finally defeat Oriana. However, Lidvia contacts them and reveals that she and St. Peter's Cross are outside the city and there's nothing they can do to stop her from activating the spell. Luckily, the Night Parade, the festival's fireworks event has started which blocks out the stars and prevents the cross from activating. As Tōma is checked into the hospital, he is visited by Index, Kuroko and Mikoto which the latter informs he has lost their bet. Meanwhile, Lidvia escapes by a private jet but is tracked down by Laura via Stiyl's rune cards and has her ejected out of the plane. Despite Laura offering to save her if she surrenders, Lidvia refuses and chooses to fall to her death while protecting the cross. At the same time, Aleister decides to take action personally due to these recent events. The next morning, Aisa is visited by Index and later, to her joy, Tōma.
Despite a chain of bad luck with his female companions during the festival, Tōma gets lucky on the last day when he wins a lottery for a one week trip to Chioggia, Italy. After he and Index arrive at Chioggia, Tōma tries to find Index after she gets lost but is found by Orsola who manages to find Index. Later, Orsola explains to them that she and the Amakusas are here at Chioggia to help move and pack her belongings to London. After helping them, Tōma and Index are about to go to their hotel when two assassins try to kill Orsola but their attempts are thwarted by Tōma and Index. The other assassin escapes by summoning a Sailing ship made of Ice in the canal where Tōma and Orsola accidentally board it. As they hide from their pursuers inside the ship, both of them realize the assassins were from the Catholic church and there is a fleet of Ice ships heading towards the Adriatic Sea. When someone tries to enter the room in which they're hiding, Tōma prepares himself and is surprised to find out it's Agnese.
Agnese explains the ship she is on is known as the Queen of the Adriatic Sea where she and her former group are being punished. She agrees to let Tōma and Orsola escape in exchange for the rescue of Luccia and Angelene, who are at risk of having their brains restructured to avoid casting a certain spell that would allow them to escape. Tōma agrees to help her rescue them, although in shaking hands, he accidentally dispels her magical clothing. As Agnese goes to the flagship to confront the squadron's leader, Bishop Biagio Busoni, Tōma and Orsola manage to find and rescue Luccia and Angelene, who tell him that Agnese is in danger of being used for a spell that would destroy her brain. Just then, the other ships start shooting at them, causing them to fall into the sea, but they are rescued by Index and the Amakusas using an underwater boat. After learning that the spell Biagio intends to use Agnese for has the power to destroys citys and erase their culture, the Amakusas agree to help Tōma and co. rescue Agnese. They launch an attack on the fleet, where they face up against an army of nuns, but when the allied ships try to sink the ship they're on with them, Angeline gets injured trying to keep one of the nuns being killed.
Lucia and the Amasukas hold off the battle nuns while Tōma, Index and Orsola continue onwards to the flagship. While Tōma distracts an army of ice golems, he soon encounters Biagio, who uses his magic enlarging crosses and gravity magic to defeat him. Meanwhile, Orsola manages to finds Agnese but is soon found by Biagio who reveals he needs Agnese so he can use the Fleet's powers to destroy Academy City. As Biagio subdues them, Tōma arrives and knocks him down. With his plans foiled, Biagio activates the Fleet's self destruction spell that will cause a large explosion. Tōma orders Orsola to escape with Agnese and the others while he fights Biagio one more time, finally defeating him and stopping the spell despite the flagship sinking. As Tōma wakes up in a hospital, he gets a call from Heaven Canceler who informs him that he is being flown back to Academy City and reminds him of Mikoto's bet for him. In London, Kaori is informed of the recent events by Motoharu and greets Orsola, who has returned with Agnese. Meanwhile in the Vatican, a nun with a pierced face from God's Right Seat forces the Pope to sign an order to investigate Tōma and eliminate him if he is seen as an enemy.
Autumn arrives at Academy City and the city's students change into their winter uniforms. Accelerator, Last Order and Kikyō move out of the hospital into Aiho's apartment, while Misaka 10032 and three other Sisters begin rehabilitation in the city. Meanwhile as promised in their bet, Mikoto has Tōma do whatever she wants, dragging him to a mobile phone shop which is offering a Gekota phone strap for those who take out a couples plan. However, in order to qualify for the offer, they have to take a photo of themselves as a loving couple, which is ruined when a jealous Kuroko intervenes. Elsewhere, Last Order gets herself locked out of the apartment which leads to Misaka 10032 making fun of her situation. Last Order is jealous that she is the only Misaka clone which doesn't have goggles, so Last Order steals and run off with Misaka 10032's goggles, which she doesn't take too kindly.
In London, the ladies of Necessarius try to learn to use a new washing machine. Back at Academy City, Mikoto finally claims her phone straps, while Tōma encounters Misaka 10032, who is searching for Last Order, and buys her a necklace so he can distinguish her from Mikoto. As Mikoto rejoins them, Misaka 10032 starts teasing her and clinging onto Tōma, attracting the attention of Last Order before Misaka 10032 chases after her again. Elsewhere, Hyōka appears from the Imaginary District and is apprehended by AntiSkill. Accelerator heads to the underground mall to look for Last Order and ends up encountering Index, who decides to help search for her after he treats her to a meal. Meanwhile, Last Order approaches Tōma to thank him for stopping the Level 6 Shift experiment, mentioning how she hopes to protect Accelerator. Tōma and Last Order soon part ways and join up with Index and Accelerator respectively, though Tōma and Accelerator don't actually see each other, and start making their way home.
In Russia, Sasha Kruezhev tries to learn the side effects of her body after Archangel Gabriel possessed her but is harass by her superior Vassilisa. As Accelerator walks Last Order back home, she trips and scrapes her knees so he goes to buy her some bandages. However, he is soon attacked by a group of armed soldiers called the Hound Dogs led by his old mentor, Amata Kihara. While Accelerator easily deals with his men, Amata, who had helped Accelerator learn his powers, knows all the tricks to negate his ability and brutally beats him up. When the Hound Dogs attempt to kidnap Last Order, Accelerator manages to muster up enough strength to blow her away to safety, before Index, who wanted to return a tissue package to him appears on the scene. Meanwhile, Tōma goes looking for Index after she went off but witnesses a group of Anti-Skill officers mysteriously falling unconscious before running into Last Order, who asks for his help. At the same time, a magician from God's Right Seat named Vento of the Front has entered Academy City and contacts Aleister that she has neutralize the Anti-Skill and Judgment forces, killed three of his Board of Directors and is planning to kill him and everyone else in Academy City. Unfazed by her threats, Aleister orders Amata to deploy "FUSE=Kazakiri" and capture Last Order to eliminate Vento.
Accelerator uses Index's presence as a distraction to force a driver to get him and Index away from the Hound Dogs. Before Amata can go after them, Vento appears and takes care of his men as he pursues after Accelerator. Meanwhile, as Tōma and Last Order search for Accelerator, they escape from the Hound Dogs chasing after her by hiding in a restaurant where everyone is also unconscious. Accelerator leaves Index in the care of Heaven Canceller, who informs him about Last Order's situation. In an attempt to take out the Hound Dogs hunting him, he lures them into a railway factory and kills them off one by one. As Tōma and Last Order continue to hide, they are confronted by Vento, whose image has caused several people, including Aiho and Kazari, to fall unconscious. Tōma defends the unconscious patrons of the restaurant from Vento's attacks and tells Last Order to run as Vento is after him but she soon starts coughing up blood and is forced to flee. Accelerator finally kills the last Hound Dog soldier hunting him but his actions have been witness by an Anti-Skill patrol unit, putting him as a wanted murder suspect. Meanwhile, Tsuchimikado is investigating Vento's actions, and comes across a white spectral being.
As Tsuchimikado battles against the spectral being who is working with Vento to kill the unconscious residents of Academy City, Tōma calls Accelerator from Last Order's cellphone to update him on her status. Accelerator soon learns that Amata has managed to capture Last Order, though is keeping her alive for some reason. Aleister then uses Testament, with Last Order's authorization, to summon an angel to appear in the city to target those who use magic. As Tōma, Mikoto and Index head towards where the angel is, Index realizes the angel is actually Hyōka. As Mikoto holds off the Hound Dogs, Index explains the nature of Vento's Divine Punishment, which targets anyone who experiences a certain emotion towards her and how Hyōka isn't an ordinary angel. Tōma tells her to work with Mikoto to combine their knowledge of magic and science to figure out how to help her. Meanwhile, Accelerator breaks into the Hound Dog's headquarters and confronts Amata. As Tōma witnesses Hyōka's controlled state and feels helpless, since using his right hand would kill her, Vento appears before him again, threatening to kill them both, so Tōma stands to defend Hyōka.
Accelerator starts to fight Amata, but the battery for his link to the Misaka Network runs out, leaving him paralyzed and defenseless. However, he begins to move again by force of will and starts to come after Amata. Meanwhile, Tōma fights against Vento, who continues to be weakened by Testament, while Hyōka makes snow appear over the city, protecting the unconscious civilians. Vento reveals her hatred towards science because both she and her little brother got into accident at a amusement park that was supposed to be the safest and the hospital only had enough blood to save her alone. Tōma argues against her reasoning for her actions and manages to punch and knock her out. Index appears in Amata's HQ and, thanks to Mikoto's knowledge of science, learns that Last Order is being used as a container to create the angel. She sings a song in order to sever the shackles controlling Last Order, which in turn resonates with Accelerator who awakens as a result and blasts Amata into the sky. In the end, Acqua of the Back from God's Right Seat appears and gives Tōma Vento's cross as her Divine Punishment has been dispelled before warning Tōma not to fight him as he is a Saint and leaves with Vento.
Thanks to Index, Hyōka returns to normal and, despite blaming herself for the chaos she caused, Tōma ensures her she also protected the city's populace. As Acqua retreats with Vento and the rest of her men from Academy City, Accelerator is captured by the City's security forces. As the city recovers from Vento's attack, Tsuchimikado and Tōma's class have dinner at a sukiyaki restaurant where they later talk about how a war will be coming to Academy City. Meanwhile, the City's Board of Directors punishes Accelerator for his actions by making him join a special Team called GROUP which compose of Tsuchimikado, Awaki and the mage who disguised himself as Mitsuki Unabara. After increasing the time limit of Accelerator's powers, GROUP first mission is to neutalzie the threat pose by the Skill-Outs, gangs of Level 0s lead by Ritoku Komaba, who are taking advantage of the lack security in the city after the Anti-Skills are forced to defend the city's outskirts to prepare themselves for more attacks by the Catholic church. As Accelerator and Awaki begin their attack at the Skill-Out's home turf, Awaki comes across Ritoku.
Despite her abilities, Awaki finds herself at a disadvantage as Ritoku is using stolen military weapons including an exo-suit called 'Hard Taping' which gives him incredible speed and strength. After defeating her, Ritoku then confronts Accelerator, using a chaff grenade to interfere with his Misaka Network link. However, Accelerator manages to use a pistol to clear the air and land a shot on him, thanks to Awaki's assistance. After killing Ritoku, Accelerator decides to do some overtime and encounters a drunk Misuzu, who is searching for the Dangai University database center for a report. After sending her off in a taxi, where she exchanges numbers with Tōma, Accelerator is contacted by GROUP's mysterious head, who reveals that they have hired the Skill-Outs to kill Misuzu as she is the Parent-Student representative who are attempting to take their children out of Academy City before the impending war. When they cut off his powers after he refuses to help the Skill-Outs, Accelerator decides to head to Dangai University to rescue Misuzu despite spotting Tōma, who also goes there to save Misuzu after she called him for help. Thanks to Accelerator's unseen aid, Tōma is able to escape with Misuzu from the Skill-Outs, only to confront by one of them named Shiage Hamazura. Shiage is desperate to kill to Misuzu as the City's higher-ups will exterminate the Skill-Outs if they fail but Tōma berates Shiage's ideals of trampling over other lives and knocks him out. As Tōma is admitted into hospital, Mizusu admits she came to take Mikoto home, but feels safe knowing there are people like him to protect her. Accelerator later meets with the rest of GROUP who reveals the order on Misuzu's life has been canceled and the four of them decide to work together so they may one day take on the higher-ups. As each of the characters spend the night in their own ways, Hyōka and Index visit the injured Tōma.