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.
Tōma Kamijō is chased by hooligans after he stops one of them from disturbing a girl. In reality he was trying save him as the girl is Level 5 Psychic Mikoto Misaka, who can control and generate electricity. After losing them, he meets Mikoto who wants a duel but he refuse citing he just a Level 0 psychic. Nevertheless, she "shoots" an electrical bolt at him but it is stop by Tōma right hand which has a power called Imagine Breaker. Angered, she attacks with a powerful lighting strike which only ends up causing a citywide blackout. The next morning, after lamenting his recent bad luck, he finds a young nun hanging outside of his veranda. After feeding her spoiled food, she introduces herself as Index, a nun from the Church of England and is being chase by magicians for she "possess" 103,000 grimoires. After both of them explain each other about their own worlds, Index doesn't believe that Tōma's right hand can nullify other powers while he doesn't believe magic exist. To test their proofs, Tōma use his powers on Index's magical garb which is unfortunately blown into pieces. After biting Tōma in revenge and fixing her garb, Index concludes that his powers are the cause of his bad luck, leaves and thanks him and he tells her to come again if she needs help. After coming back from summer classes, he meets Mikoto again who wants a rematch but when he refuse again, she stomps her foot in anger causing nearby electronics to go haywire including cleaning bots who sounds the alarm which forces both of them to quickly runaway. When he returns home, he finds Index laying on the ground bleeding and behind him a man who calls himself a magician.
The magician reveal himself as Stiyl Magnus and explain that his partner Kaori unintentionally hurt Index as her Magical garb was suppose to stop the blow and his mission to 'protect' Index or actually the Index-Librorum-Prohibitorum, the 103,000 books implanted in her mind as she possess photographic memory. Toma, angered by Stiyl's ill treatment of Index attacks him and he counterattack by using Fire magic but is surprised when Toma nullify s the spell. Styil then summons a fire creature named Innocentius which Toma can't stop as the creature keeps regenerating itself from his attacks. It is only when Index other personality, John's pen mode, reveals the creatures powers comes from Runes place around the building that Toma is able improvise and defeat Innocentius and Stiyl using the sprinklers to destroy the Runes as they were on paper and rescue Index. When he learns from Index that he can't help heal her wounds using magic as it can only be use by normal people, Toma brings her to the only normal person he knows for help, his teacher, Komoe Tsukuyomi.
While Komoe helps Index in healing her wounds using magic, Toma meets Stiyl's partner, Kaori Kanzaki and learns from her why they are hunting Index and the organization, Necessarius, The Church of Necessary Evil.
Touma learns the truth about Index's perfect memorization and her loss of memories.
Touma tries desperately to save Index's memories before it is too late.
Following the events of last episode and the activation of Index's defense mechanism Touma struggles to hide his amnesia from Index.
Stiyl and Touma join forces to investigate the mysterious Misawa Cram School.
Touma encounters Ars Magna the leader of Misawa Cram School and a man with his own connection to Index.
Touma confronts Ars Magna in a dangerous battle to rescue both Index and Deep Blood.
Touma spends some time with Misaka Mikoto and makes a strange discovery.
Touma goes in search of Misaka to investigate the clone experiment.
Touma discovers the reason behind the experiment and appears to grow closer to Misaka.
Misaka and Touma hatch a plan to defeat Accelerator and end the experiment.
Touma faces off against Accelerator for the sake of Misaka and her 'sisters'.
Touma and Index head to the beach to avoid the fallout from Touma's fight with Accelerator. They also plan to meet Touma's Family but when they arrive they aren't quite what Touma was expecting.
The Angel Fall spell remains in effect with only Toma, Kanzaki, Misha and Tsuchimikado relatively unaffected. However, the person responsible for casting the spell remains a mystery. Misha quickly becomes the prime suspect after a strange conversation with Toma. But when Toma follows up on his hunch he discovers that the real culprit is not Misha but his own father. As such he hurries to reach his father before Misha and the other mages can confront him.
Tōma confronts his father about casting Angel Fall but discovers him as knowing absolutely nothing about it. When Misha appears to them, Kaori reveals that Misha is an imposter taking advantage of her appearance as Sasha Kruezhev, a member of Annihilatus. Misha subsequently reveals herself to be one known as "Power of God", Archangel Gabriel, the Angel who fell as a result of Angel Fall being cast, and uses her power to complete a spell to destroy the world so that she may return to Heaven. Kaori sends Tōma and his father to destroy the ritual site while she holds off the Angel. Tsuchimikado reveals that the ritual site is actually the Kamijōs' new residence and that Tōma's father accidentally cast the spell from coincidentally arranging occult souvenirs around the house in a particular way. When Tsuchimikado reveals that he's going to destroy the source of Angel Fall, Tōma tries to stop him from killing his father, but he knocks out Tōma's father and beats up Tōma so that he is unable to move. In a sudden twist, Tsuchimikado decides to sacrifices himself to cast a spell to destroy the ritual site (despite knowing he will die using magic), which causes Misha/Gabriel to return to Heaven. When Tōma returns to the hospital again, he finds Tsuchimikado alive and well despite using magic after becoming an esper (much to his surprise), thanks to his psychic healing ability, Auto Rebirth. Tsuchimikado also reveals that he is not only a spy for Necessarius but also a freelancer for Academy City and other organizations. As an apology, he brings Tōma's parents to visit him, but Tōma is outraged to learn that his family's new house was completely destroyed by Tsuchimikado's spell and then must suffer Index's wrath for being mistreated by Tōma while she was under the spell.
Mikoto's trying to enjoy her last day of summer vacation, but she is being stalked by Mitsuki Unabara, the Tokiwadai Middle School principal's grandson who's been chasing her since last week. In an attempt to make him give up, she pretends to go on a date with Tōma. During their fake date, Tōma learns that only 10 of the Sisters remain at Academy City while the rest went overseas for treatment. Tōma converses with Unabara but is surprised to see another person who looks exactly like the latter running into a restaurant that Mikoto has entered. As the second and injured Unabara warns Mikoto about an approaching danger, the first Unabara remarks to Tōma about espers who can shift appearances, and Tōma realizes that he is conversing with an imposter when the latter tries to hit him from behind. As Tōma flees, Index reveals by phone that the imposter is using the magic of Aztec priests to disguise himself with another person's skin and wields an obsidian spearhead as a replica of the lance of Tlahuizcalpantecuhtli. When Tōma is forced to fight him, the imposter reveals that he had been sent to become close to Tōma's friends (such as Mikoto) to prevent the formation of the "Kamijō Faction", a group of mages and espers lead by Tōma which both the magic and science sides fear will destroy the truce between them. Since the imposter had fallen in love with Mikoto, he decided to protect her by killing Tōma, but, now defeated and severely injured, he asks Tōma to promise him to protect her since they'll be others like him after Tōma and his friends. Unknown to both of them, Mikoto is listening nearby and is embarrassed to hear Tōma's answer.
Since his defeat, Accelerator is no longer feared by others, though he remains powerful enough to get rid of troublemakers. During the last day of summer vacation, he is approached by a younger Misaka clone capable of showing emotions, who introduces herself as "Last Order" and begins to follow him around, much to his annoyance. Because she is hungry, Accelerator takes Last Order to a restaurant and sees Ao Amai, a former researcher for the "The Sisters" project, but does not pursue him. As Last Order eats, she converses with Accelerator on the Sisters and how she believes that Accelerator was an unwilling participant of the Level 6 Shift project. Tired of her comments, Accelerator leaves her at the restaurant to confront Yoshikawa, a researcher in charge of the Level 6 Shift project. She informs him that Last Order was not created for the Sisters project but for administrating the Misaka Network and that Ao Amai injected a virus into Last Order, which could spread to the other Misakas and cause them to go berserk and attack humans. To stop the virus, she gives Accelerator the choice of finding Ao Amai to explain how to stop the virus or returning Last Order to her incubator. Accelerator chooses the latter.
Accelerator returns to the diner only to find that Last Order has been kidnapped by Ao Amai. Accelerator manages to track down Ao Amai and knocks him out before he can escape with Last Order. However, the virus in Last Order activates earlier than expected and Yoshikawa is still en route with Last Order's incubator. To stop the virus, Accelerator uses his powers and a clean copy of Last Order's data to remove the virus. However, nearing the end of the process, Amai awakens and shoots Accelerator in the head; Accelerator is unable to fully stop the bullet, having chosen to finish removing the virus instead of protecting himself, and collapses afterward. Amai tries to finish him off but is shot by Yoshikawa who has arrived to put Last Order into her incubator. After discussing their roles as researchers and her dream of wanting to become a teacher, she and Amai shoot each other. When Yoshikawa awakens in the hospital, she learns from Heaven Canceller, who is none other than Tōma's frog-faced doctor, that Accelerator saved her but suffers from brain damage from the shot he took while saving Last Order and needs rehabilitation to regain his powers.
Tōma returns to school after summer break, but is followed by Index, who thinks she won't have anything to eat for lunch while he's away at school. When Index arrives in class, Komoe sends her away with money to ride a taxi home and then introduces Aisa as a new transfer student. Index ends up befriending Hyoka Kazakiri, another transfer student; Tōma later finds them trying to change into less conspicuous clothing and when Komoe catches Tōma skipping the opening ceremony, Hyoka mysteriously vanishes. Aisa becomes suspicious of Hyoka, who was a student at Aisa's old school, and warns Tōma and Komoe about her. Meanwhile, Tsuchimikado meets with Aleister Crowley concerning the arrival of Necessarius mage Sherry Cromwell in Academy City and despite Tsuchimikado's offer to take care of Sherry discreetly, Crowley wants Tōma to defeat her. Meanwhile, Kuroko finds Sherry and attacks her unsuccessfully, but is saved by Mikoto while Sherry escapes and casts a spell to send eyeballs throughout the city.
Sherry Cromwell begins her assault on Academy City to start a war between Necessarius and Academy City. As a result, Tōma, Index, and Hyoka are locked in an underground shopping complex before they are evacuated with everyone else. Mikoto and Kuroko find them and Kuroko teleports Mikoto and Index, who become suspicious of the other's relationship with Tōma, away first. When Tōma hears an explosion, he goes to confront Sherry and leaves Hyoka to wait for Kuroko to return. As he tries to fight Sherry's golems, Hyoka arrives, but is hurt and Tōma ends up seeing a strange device in her head. When she flees, Sherry decides to pursue her while Tōma gets a call from Komoe, who explains that Hyoka's existence likely came to being from the collective extranaeous discharge of espers in the city. Meanwhile, Hyoka manages to regenerate her face, but Sherry, who knows Hyoka isn't human much like her golems, is about to crush Hyoka when Tōma appears and saves her.
Tōma stops and successfully destroys Sherry's golem with Imagine Breaker. When she summons another one,Tōma coordinates with the Anti-Skills to put her on the defensive. Sherry attempts a simultaneous summoning of Ellis, destroying the ground beneath her and escaping. Wondering why Sherry would turn to escape so quickly when her target, Hyōka, was right in front of her causes Tōma to realize that her true target was Index all along. Chasing after a runaway Sphinx, Index is attacked by Ellis. At first she is able to hold her own against the remote controlled Ellis by interfering with the control mechanism, when Ellis switches to automated control things turn worse. Index can only call Tōma's name as Ellis prepares to crush her.
Tōma pursues Hyōka but encounters Sherry instead and is forced to fight her. He learns that Ellis was once a friend of Sherry who suffered painful consequences from an attempt by Necessarius and Academy City to reconcile magic and science; to prevent this tragedy from occurring again, Sherry intends to divide them forever through conflict. Outraged that Sherry does not believe that people who are different like Index and Hyōka could be friends, Tōma successfully defeats Sherry. However, doing so results in Golem Ellis above ground losing control, and Index is cornered until Hyōka suddenly appears and destroys the Golem each time it reforms. After Tōma arrives to deliver the finishing blow, Index and Hyōka reconcile just as Hyōka fades away to the Imaginary Number Sector. Meanwhile, Tsuchimikado confronts Aleister Crowley on why he is interested in the Imaginary Numbers Sector. As each of the characters settle back into their daily lives, Stiyl meets with the Archbishop of Necessarius, Laura Stuart, who decides that Necessarius will need Index and Tōma's help for an upcoming problem meanwhile Kaori Kanzaki is missing in Japan after the events of the Angel Fall.