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In 2015, 15 years after a global cataclysm called the Second Impact, teenager Shinji Ikari is summoned to the futuristic city of Tokyo-3 by his estranged father Gendo Ikari, who is the director of the special paramilitary force Nerv. Shinji witnesses United Nations forces battling an Angel, one of a race of monstrous beings whose awakening was foretold in the Dead Sea Scrolls. Because of the Angels' near-impenetrable force-fields, Nerv's Evangelion bio-machines, which are synchronized to their pilots' nervous systems and possess their own force-fields, are the only weapons capable of fighting the Angels. Nerv officer Misato Katsuragi escorts Shinji into the Nerv complex beneath Tokyo-3, where Gendo pressures him into piloting Evangelion Unit-01 against the Angel. Without training, Shinji is quickly overwhelmed, causing the Evangelion to go berserk and savagely kill the Angel on its own.
Following hospitalization, Shinji moves in with Misato and settles into life in Tokyo-3. In his second battle, Shinji defeats an Angel but runs away afterward, distraught. Misato confronts Shinji, and he decides to remain a pilot. Shinji and Nerv's crew must defeat the remaining fourteen Angels to prevent the Third Impact, a global cataclysm that would destroy the world. Evangelion Unit-00 is repaired shortly afterward, and Shinji tries to befriend its pilot Rei Ayanami, a mysterious and socially isolated teenage girl. With Rei's help, Shinji defeats another Angel. They are joined by Evangelion Unit-02's pilot, the multitalented but insufferable teenager Asuka Langley Sōryu, who is German-Japanese-American. The three of them manage to defeat several Angels, and as Shinji adjusts to his new role as a pilot, he gradually becomes more confident and self-assured. Asuka moves in with Shinji, and they begin to develop confusing feelings for one another, kissing at her provocation.
After being absorbed by an Angel, Shinji breaks free thanks to Eva-01 acting on its own. He is later forced to fight Evangelion Unit-03, who has become infected, and its pilot, his friend and classmate Toji Suzuhara, becomes incapacitated and permanently disabled. Asuka loses her self-confidence following a defeat and spirals into depression, which is worsened by her next fight against an Angel who attacks her mind. It forces her to relive her worst fears and childhood trauma, resulting in a mental breakdown. In the next battle, Rei sacrifices herself to self-destruct Unit-00 and save Shinji. Misato and Shinji visit the hospital, where they find Rei alive, but claiming she is "the third Rei". Misato forces the scientist Ritsuko Akagi to reveal the dark secrets of Nerv, the Evangelion boneyard, and the Dummy Plug system, which operates using clones of Rei, who was created using the DNA of Shinji's mother, Yui Ikari. This succession of events leaves Shinji emotionally scarred and alienated from the rest of the characters. Kaworu Nagisa replaces the catatonic Asuka as Unit-02's pilot and befriends Shinji, gaining his trust. He is revealed to be the final foretold Angel, Tabris, and fights Shinji, realizing that he must die to allow humanity to survive. He asks Shinji to kill him, and he hesitates but eventually kills Kaworu; an event that causes him to be overridden with guilt.
After the final Angel is defeated, Gendo triggers the "Human Instrumentality Project", a forced evolution of humanity in which the souls of mankind are merged for benevolent purposes. He believes that if unified, humanity could overcome the loneliness and alienation that has eternally plagued them. Shinji's soul grapples with the reason for his existence and reaches an epiphany that he needs others to thrive and to accept himself by seeing a potential Shinji in another reality. This enables him to destroy the wall of negative emotions that torment him and unites with the others, who congratulate him.