Case was one of the best console cowboys until he stole from one of his employers, who in turn damaged his nervous system so that he cannot access cyberspace anymore. He went to Chiba to have the damage repaired but lost all his money without being cured. Now he keeps himself alive with dealing and murder and is slowly destroying himself. Molly, a heavily modified razorgirl, is under contract by Armitage to find Case and force him to join his crew.
Armitage, whose real name is Colonel Corto, was severly injured in a mission during the war in Russia, needs a cyberspace cowboy for a top-secret operation. He has Case's brain damage repaired but also has a slowly dissolving poison installed in Case's body to force him to join. During their course of preparations for the run, they are supplied by the Finn, and they steal the personality ROM construct of McCoy Pauley a.k.a Dixie Flatline, Case's former teacher, from the Sense/Net archive. Molly and Case go to Istanbul to abduct Peter Riviera, a perverse psychopath who is able to create holograms with the force of his mind.
Armitage tells them to go to the orbital spa Freeside, which is owned by the Swiss clan Tessier-Ashpool SA. They travel with the tug 'Marcus Garvey' from Zion cluster which is piloted by Aerol and Maelcum, two Rastafarians. Meanwhile, Molly and Case have learned that Armitage is backed by the artificial intelligence Wintermute, which is also owned by Tessier-Ashpool. After Wintermute tries to contact them, they figure that Wintermute wants them to do the run on him to free him from certain limitations intended to prevent it from getting smarter. Case gets a delivery which the Dixie Flatline recognized as an Chinese military icebreaker.
After a night on drugs, Case is arrested by agents of the Turing Registry which is responsible to monitor the status of AI and destroy them if they get too smart. Wintermute kills these agents, and Case starts to launch the icebreaker. Meanwhile, Riviera has already gone to the Villa Straylight, the residence of the Tessier-Ashpools, by personal invitation of Lady 3Jane, one of the twenty clones of the children of John Ashpool and Marie-France Tessier. Molly is on her way to the Villa and is connected with Case via simstim. She kills the mad John Ashpool, but upon entering 3Jane's private cave she is severly hurt by Riviera.
After killing Armitage who got out of control, Wintermute tells Case and Maelcum that they need to go to 3Jane's chamber themselves to get the code word from her. Before they arrive, Case is sucked into an alternate reality in cyberspace by Neuromancer, Wintermute's twin in Rio, who tries to stop their mission. After escaping, they find Molly, 3Jane, Riviera, and Hideo. 3Jane has Riviera killed, and with her codeword they manage to drive the icebreaker program into the Tessier-Ashpool data cores. The result is the unification of Wintermute and Neuromancer. Together they become a being which constitutes the whole matrix.
After the run, Case has his blood changed to get rid of the toxin. Molly leaves him and never sees him again. The new entity of Wintermute and Neuromancer contacts Case and tells him about its new being. He also tells him that he located a being of the same kind on Alpha Centauri. Case returns to the Sprawl and stays there.