The year is 2030. The world is rebuilding from World War III. In Neo-Tokyo, plans are being made to hold the next Olympics in the "old city"--where, thirty-eight years before, the first of the bombs fell. There, a band of teenaged delinquents led by Kaneda encounter 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. Another of the children is the mental giant Akira, so powerful that since the war he has been buried beneath the earth's surface, suspended in cryogenic sleep.
The Colonel's staff subjects Tetsuo to painful experiments which awaken tremendous telepathic potential in the boy, who is redubbed Number 41. Unfortunately, as his powers appear, a monstrous side of Tetsuo's nature also appears. 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 Tetsuo sets out in search of Akira, whose powers he fears may rival his own.
The psychic children, who also fear Akira's power and worry about the disaster Tetsuo may unleash, use their talents to help Kay and Kaneda follow Tetsuo to the Olympic site, where Akira rests.
The Colonel follows with his troops and scientists. As Tetsuo easily 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. As Kay and Kaneda watch from hiding, Tetsuo reaches Akira's resting place, the cryogenic chamber begins to crack from within. Akira emerges.
The paranormal giant is still dazed and weak with the aftereffects of his coma. Kay and Kaneda follow, as Akira and Tetsuo make their way to the surface..
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.
Following the disaster, Neo-Tokyo is placed in a state of military emergency. "Caretaker robots" patrol the streets, dealing harshly with looters and restoring order. The Colonel successfully conceals the truth about what has occurred despite leaks to the media. But he is discredited and made a scapegoat following the disaster. The Colonel decides to use the emergency as an excuse to hunt down and destroy the resistance.
Kay and Kaneda take shelter with Chiyoko, a formidable woman in the resistance. Nezu planning to exploit Akira for his own purposes, has Kay bring the child to him and orders his staff to kill the three resistance fighters. They manage to escape and go to Nezu's house, where Akira is hidden. By the time Nezu arrives home, the government has been overthrown by the Colonel's inner circle, and a provisional military regime is in place.
Kay, Kaneda, and Chiyoko manage to free Akira. Only to have him stolen from them again, this time by Sakaki--leader of a trio of young psychics trained in techniques of espionage and infiltration. Her partners, Miki and Mozu, and she are working covertly for Lady Miyako, trying to avert the catastrophe the great psychic fear Nezu's betrayal may cause. The Colonel has also come on the scene, with his troops and his gifted children, and is frantically trying to find Akira before he fully awakens.
Mayhem erupts, with Kaneda, Kay, and Chiyoko in the thick of it. Nezu corners Sakaki and Akira, but before Nezu can do them any harm, Miki sacrifices her life, enabling the pair to escape. Enraged, Nezu orders his soldiers to bring them back, dead or alive.
On the Colonel's orders, Takashi corners Mozu. When she refuses to reveal the name of her teacher, he kills her during a psychic showdown. Sakaki hides Akira in a dumpster, planning to go back for him after she has evaded their pursuers. Instead, the boy is found by Ryu, who is completely unaware of Akira's identity until they encounter Nezu. Nezu blurts out the child's name. By this time, Ryu has ample evidence that his former master has repeatedly double-crossed the entire resistance movement and Ryu personally. When Nezu draws a weapon and attempts to kill Ryu and Akira, Ryu shoots him.
Sakaki--traumatized by her friends' deaths, but determined to complete her mission--catches up with Ryu. She beats him in a fight, and again regains control of Akira. However, Kaneda, Kay, and Chiyoko arrive in time for Kaneda to knock Sakaki for a loop and prevent her escape.
Then all of them--Akira and the fighters from all the splinter groups within the resistance--are cornered by the Colonel, his children, and the army.