Henry Dorsett Case is a low-level hustler in the dystopian underworld of Chiba City, Japan. Once a talented computer hacker and "console cowboy", Case was caught stealing from his employer. As punishment, Case's central nervous system was damaged, leaving him unable to access the virtual reality dataspace called the "matrix". Case is approached by Molly Millions, an augmented "razorgirl" and mercenary on behalf of a shadowy US ex-military officer named Armitage, who offers to cure Case for his services as a hacker. Case agrees, and his nervous system is repaired, though sacs of poison are placed in his blood vessels. If Case completes the job, Armitage will have the sacs removed; if not, they will burst and cripple him again.
Armitage has Case and Molly steal a ROM module that contains the saved consciousness of one of Case's mentors, legendary cyber-cowboy McCoy Pauley.
Case and Molly discover Armitage's former identity as Colonel Willis Corto. Corto was a member of "Operation Screaming Fist," meant to disrupt Soviet computer systems. As his team attacked a Soviet computer center, EMP weapons shut down their flight systems. He and a few survivors escaped over the Finnish border, but their helicopter was shot down, killing everyone except for Corto. After months in a hospital, Corto was visited by a US government official, who returned him to the United States to receive psychotherapy and reconstructive surgery. After providing what he came to realize was false testimony, misleading the public and protecting corrupt military officers, Corto snapped, killed the official who contacted him, and disappeared into the criminal underworld, becoming Armitage.
In Istanbul, the team recruits Peter Riviera, a sociopathic thief and drug addict. The trail leads Case to Wintermute, an artificial intelligence created by the Tessier-Ashpool family. The Tessier-Ashpools spend their time in cryonic preservation at Freeside, a cylindrical space habitat which functions as a Las Vegas-style space resort for the wealthy.
Wintermute reveals itself to Case and explains that it is one half of a super-AI entity planned by the family. It has been programmed with a need to merge with its other half, Neuromancer, and has recruited Armitage and his team since it cannot achieve this goal by itself. Case is tasked with entering cyberspace to pierce the software barriers with an icebreaker program. Riviera is to obtain the password to the lock from Lady 3Jane Marie-France Tessier-Ashpool, the CEO of the family's corporation.
Armitage's personality starts to revert to the Corto personality as he relives Screaming Fist. It is revealed that Wintermute had originally contacted Corto through a computer during his psychotherapy, creating his Armitage persona. As Corto breaks through, he is uncontrollable, and Wintermute ejects him into space.
Riviera meets Lady 3Jane and tries to stop the mission, helping Lady 3Jane and Hideo, her ninja bodyguard, capture Molly. Under orders from Wintermute, Case tracks Molly down. Neuromancer traps Case within a simulated reality after he enters cyberspace. He finds the consciousness of Linda Lee, his girlfriend from Chiba City, who was murdered by one of his underworld contacts. He also meets Neuromancer, who takes the form of a young boy. Neuromancer tries to convince Case to remain in the virtual world with Linda, but Case refuses.
With Wintermute guiding them, Case goes to confront Lady 3Jane, Riviera, and Hideo. Riviera tries to kill Case, but Lady 3Jane is sympathetic towards Case and Molly, and Hideo protects him. Riviera flees, and Molly explains that he is doomed anyway, as she had spiked his drugs with a lethal toxin. The team makes it to the computer terminal. Case enters cyberspace to guide the icebreaker; Lady 3Jane is induced to give up her password, and the lock opens. Wintermute unites with Neuromancer, becoming a superconsciousness. The poison in Case's bloodstream is washed out and he and Molly are profusely paid, while Pauley's ROM construct is apparently erased at his own request.
Molly leaves Case, who finds a new girlfriend and resumes his hacking work. Wintermute/Neuromancer contacts him, claiming it has become "the sum total of the works, the whole show" and is looking for others like itself. Scanning recorded transmissions, the super-AI finds a transmission from the Alpha Centauri star system.
While logged into cyberspace, Case glimpses Neuromancer standing in the distance with Linda Lee, and himself. He also hears inhuman laughter, which suggests that Pauley still lives. The sighting implies that Neuromancer created a copy of Case's consciousness, which now exists in cyberspace with those of Linda and Pauley.
