Twenty-thirty. The world stands poised at the edge of World War IV. An explosion of thermo-nuclear proportions has been set off in Neo-Tokyo. The world, particularly the super powers, wonders what has happened. In Neo-Tokyo in a section known as the "old city", a band of teenaged delinquents led by Kaneda encountered Number 26, a child named Takashi who uses extraordinary telekinetic abilities to injure Tetsuo, one of Kaneda's close friends.
As a result Kaneda and Tetsuo become entangled in a power struggle between a mysterious military and scientific organization led by a man known only as the Colonel and an underground resistance group bent on putting a stop to the Colonel's activities.
Among the resistance, Kaneda meets Kay--a girl he alternately maddens and tries to seduce--and Kay's "brother", Ryu. Other important resistance members include Ryu's superior, the opposition party leader Nezu, and a powerful religious leader with precognitive gifts, Lady Miyako.
The Colonel has a number of children like Number 26 under his control. Each child possesses a distinct set of psychic talents and is identified by a number marked on the hand. At one time Lady Miyako was Number 19 in this series. Number 28 is Akira, so powerful that since the war he has been suspended in cryogenic sleep.
The Colonel's staff conducts experiments which awaken tremendous telepathic potential in Tetsuo, who is redubbed Number 41. Able to shrug off the most serious injuries, Tetsuo goes on a killing spree, murdering one of Kaneda's friends and even attacking Kaneda. Then, followed by Kay and Kaneda, Tetsuo sets out in search of Akira, whose powers he fears may rival his own.
Tetsuo repels soldiers armed with the most sophisticated weaponry. The scientists monitoring Akira's cryogenic sleep realize that even in hibernation, Akira's power is responding to Tetsuo's psychic energy. When Tetsuo reaches Akira's resting place, the cryogenic chamber begins to crack from within. Akira--dazed and docile following his long sleep--emerges.
Terrified of what may occur, the Colonel summons the powerful SOL military satellite and orders that its laser cannon be fired at Tetsuo and Akira. The two are separated by the blasts. Akira is saved by Kay and Kaneda, but Tetsuo is less fortunate. The laser strikes his left arm.
Neo-Tokyo is placed in a state of military emergency following the disaster. "Caretaker robots" patrol the streets, dealing harshly with looters and restoring order. Discredited and made a scapegoat following the disaster, the Colonel--who successfully conceals the truth about what has occurred despite leaks to the media--decides to use the emergency as an excuse to hunt down and destroy his enemies. With the aid of his inner circle, the Colonel stages a successful coup d'etat.
Nezu, planning to exploit Akira for his own purposes, kidnaps the child and orders his staff to kill Kaneda, Kay, and Chiyoko, who nevertheless manage to escape and free Akira. He is, however, stolen from them again, this time by Sakaki, Miki and Mozu-- young psychics trained by Lady Miyako, who now knows that Nezu has betrayed her. The Colonel, with his troops and his psychic children, is also frantically trying to find Akira before he fully awakens. On the Colonel's orders, Takashi kills Mozu during a psychic showdown. Nezu corners Sakaki and Akira, but before he can do them any harm, Miki sacrifices her life, enabling the pair to escape. Sakaki hides Akira in a dumpster. There he is found by Ryu--one of the few people who doesn't recognize the child. Ryu and Akira encounter Nezu, who blurts out the boy's name. Ryu realizes that his former master is a traitor. When Nezu tries to kill them, Ryu guns him down and leaves him for dead.
As Sakaki and Ryu fight for control of Akira, they are suddenly joined by Kaneda, Kay, and Chiyoko. Then all six of them are surrounded by the Colonel's troops. Sakaki makes a last ditch effort to escape and is killed, her spirit embraced by Lady Miyako as she dies. Takashi fondly greets Akira and reintroduces him to their fellow psychics Kiyoko and Masaru. Then, Nezu, dying and determined on revenge, arrives and tries to kill Akira, killing Takashi instead.
The trauma of Takashi's death galvanizes Akira who fully awakens and unleashes a light blast powerful enough to devastate the entire city. Acting quickly, Masaru and Kiyoko sweep most of the people in the area upward, into the shelter of a skyscraper. The entire resistance group is separated, and Kaneda is last seen vanishing towards the sky. In the wake of the disaster, Lady Miyako opens her temple and offers shelter and comfort to those in need.
Afterwards, as Akira sits alone, telekinetically playing with bits of rubble, Tetsuo finally reappears.
The waters have receded from the city of Neo-Tokyo revealing the wounds below. Once gleaming skyscrapers lean at dizzying angles, their jagged, pitted facades gaping stupified at the sky. In the canyons of these buildings, surrounded by their rubble, huddle the cold, the hungry, the hurt, the dying--and the countless dead. For the dazed people left in Neo-Tokyo it is a daily struggle just to survive. There is the gentle Lady Miyako who has thrown open her temple doors to those who seek refuge. And in the west there is talk of a god-like figure who tends to the hungry and has been seen healing the injured--the Emperor Akira.