It's been a thousand years since the Gauna, a strange alien race with no known method of communication, destroyed the solar system. A portion of humanity managed to escape using enormous "seed ships" like the Sidonia, which have allowed them to maintain the population while drifting through space. Nagate Tanikaze is a young man who has been raised deep in the bowels of the ship. When he goes into training to pilot the huge robotic weapons known as Gardes, Nagate is entrusted with piloting the legendary unit known as Tsugumori. Nagate and his fellow pilots put their lives on the line against the Gauna, in the ultimate battle for the survival of humanity!
Kunato and Mozuki discover Ochiai's abandoned lab and fall into a trap resulting in their bodies hijacked by parasites. Now under Ochiai's control, Kunato and Mozuki visit Numi's lab and put her body under control of a parasite as well. When Nagate visits the Placental Shizuka, he learns that she was moved to a new location for research and that he can not see her again. He then turns to Kunato for answers, but to no avail. Meanwhile a massive Mauna approaches Sidonia and Nagate joins the sortie against it, piloting his new guardian, the "Tsugumori Kai". However the attack fails to break through the enemy's upgraded placenta. But then another Gauna-like creature appears, and with a single shot it causes massive damage to the giant Gauna. The new mysteriuos Gauna introduces itself as Tsumugi Shiraui.
A brutal attack of the Chimera, the new Human-Gauna Hybrid, destroys the remains of the Giant Gauna. Captain Kobayashi seems to be in league with Kunato (Ochiai) and other infested Sidonia crew members. The Chimera, Tsumugi Shiraui, introduces herself to the Sidonia crew as a human mind controlling a Gauna vessel. However Ochiai's experiments with Human-Gauna hybrids almost destroyed the Sidonia 100 years ago. Tsumugi Shiraui responds emotionally strong to Tanikaze's presence. Because of Captain Kobayashi involvement with the Chimera project, the Sidonia supreme council decides to remove her from here position. However before they can make this happen Ochiai’s clone murders the entire supreme council.
Captain Kobayashi announces that Sidonia will set course for the Lem Star System, pursuing the Gauna's mothership who threatens the colonists at planet Lem VII. Just when Guimera Tsumugi is about to sort for a joint exercise, she detects a large Gauna formation approaching Sidonia. At the advise of Kunato and direct orders from the captain she departs to attack it alone. However, the Gauna create a massive structure to trap her. A platoon of Guardian Pilots sortie to rescue the Guider from the Gauna.
Tsumugi manages to escape the trap the Gauna set for her, but as a result she goes into a raging attack frenzy. The massive G550 Gauna formation fires a Higgs paricle beam straight at the Sidonia, the shot is deflected by Tsumungi who was returning Izana back to the Sidonia. When Nagate launches his propulsion system into the G550 core he provides opportunity for the Gardes fighters to strike a final blow. But after this moment of victory he receives a distress call from Izana...
Rescued and back on the Sidonia Izana has her right arm and left leg replaced with prostetic limbs. The also badly wounded Tsumugi is put in a special regeneration chamber. Meanwhile, Sidonia starts to decelerate to enter the Lem Star System and rendezvous with surviving colonists. Nagate and Izana find a way for the recovered Tsumugi to get closer to the residents onboard the Sidonia. Negate has lost his rookie living space since a new trainee has been assigned to his old room, he turns to Izana for help.
Nagate chooses a new living space at the outer wall with easy tunnel acces for Tsumugi. He also asks Izana to move in with him. The new upgraded Gardes propulsion system needs testing, however it can still not match the hybrid's acceleration and speed. The captain is testing an experimental beam weapon, which has been designed and build using hybrid Gauna technology. The Graviton beam cannon is fired succesfully at a small dwarf planet, however the used Gauna placenta seems to have a mind of its own.
The Gauna Higgs particle beam cannon self- destructs causing a rupture in Sidonias armored hull. Although the risk with this hybrid technology is high, the captain wants to proceed with the research program and harness the power of this weapon at any cost. A new system which enables linking multiple Gardes, indicates a direct head on attack is approaching. Tanikaze is unaware of several love interests that are attracted to him, he especially is not aware of Izana. The colonist at planet 7 come in deadly first contact with the Massive Gauna cluster.
While the Gardes are on repair duty, Tsumugi shows of her maneuvering skills and of course not all goes well. Yuhata decides to move in with Nagate and Izana, which is a surprise too all the friends. Izana is asked to test a direct link between her bionic implants and the Gardes control system. The test is successful and should give her more "Tsumugi like" control. And the romance between Nagate and Izana starts to bloom.
Nagate and Izana continue their visit while Yuhata and Tsumugi find a way to eavesdrop on them. Izana soon discovers that Nagate was set up by her grandmother. Meanwhile Sidonia arrives at the Lem Star System. A reconnaissance party of four pilots is send out, acompanied with a new propulsion and weapon system " the Hayakaze", to scout planet Lem IX. Izana is assigned last minute as a replacement pilot. In Lem IX orbit Izana detects an unknown object which is revealed of being a new type of armored Gauna. Both Nagate and Tsumugi watch the mission feed helplessly as Izana and her team struggle against it.
Izana's squad fight for their lives against the Gauna while on Sidonia Tsumugi and Nagate request for permission to rescue them. Nagate is entrusted with a new prototype Guardian the "Tsugumori Mark III". Meanwhile Izana and a pilot with callsign 064 enter the atmosphere of Lem IX using one of the Hayakaze's pieces as a heat shield while being pursued by the Gauna. Izana realizes that the Gauna are attracted to the artificial Kabi and Higs particles. After ejecting here power core the are no longer pursued, but powerless adrift in the Lem IX atmosphere. The rescue party consisting of Nagate and Tsumugi easily take out all encountered Lem IX enemy opposition until they encounter a Benisuzume-type Gauna. Tsumugi decides to confront the Benisuzume alone, so Nagate can keep searching for Izana.
Nagate is looking for Izana who encounters some "ground" based Gauna. Nagate manages to save her just in time, but he now has to stand of against multiple attacking Gauna. He soon runs out of ammunition, but the Mark III has some special swords equipped, which uses to their fullest capability. The battle between Tsumugi and Benisuzume almost proves that Tsumugi is the better hybrid, but a moment of hesitation on Tsumugis side turns the favor to Benisuzume. It is Nagate who has to safe Tsumugi from total destruction, but Benisuzume quickly figures out the design flaw in the Mark III. Fighting blind without his systems and with placenta entering his cockpit Nagate is going to encounter a new horror........
Placental copy Shizuka entered Nagates cockpit and restrains him, Izana hacks into the Tsugumori's systems to allow Nagate to deal a killing blow on the Benisuzume, leaving the Shizuka copy dormant in his cockpit. Once Nagate releases Tsumugi, all the Gauna located on the planet converge arround them. A rescue party from Sidonia with Hayakaze-equipped pilots wipe out all the enemy forces. With his cockpit damaged, Nagate is force to return to Sidonia where Shizuka copy is put into containment. As Nagate is condecorated for his bravery, Lala approaches Kobayashi and urges her to stop using him for her plans. Meanwhile, Kunato, glimpsing an incomplete chimera, claims that his main goal is at hand. Nagate leaves behind his honorary medal at the place he was raised by his grandfather. And then he and his friends are once again called to sortie.