Henry Dorsett Case is a low-level hustler in the dystopian underworld of Chiba City, Japan. Once a talented computer hacker, Case was caught stealing from his employer. As punishment for his theft, Case's central nervous system was damaged with a mycotoxin, leaving him unable to access the global computer network in cyberspace, a virtual reality dataspace called the "Matrix". Unemployable, addicted to drugs, and suicidal, Case desperately searches the Chiba "black clinics" for a miracle cure. Case is saved by Molly Millions, an augmented "street samurai" and mercenary for a shadowy ex-military officer named Armitage, who offers to cure Case in exchange for his services as a hacker. Case jumps at the chance to regain his life as a "console cowboy," but neither Case nor Molly knows what Armitage is really planning. Case's nervous system is repaired using new technology that Armitage offers the clinic as payment, but he soon learns from Armitage that sacs of the poison that first crippled him have been placed in his blood vessels as well. Armitage promises Case that if he completes his work in time, the sacs will be removed; otherwise they will dissolve, disabling him again. He also has Case's pancreas replaced and new tissue grafted into his liver, leaving Case incapable of metabolizing cocaine or amphetamines and apparently ending his drug addiction.
Case develops a close personal relationship with Molly, who suggests that he begin looking into Armitage's background. Meanwhile, Armitage assigns them their first job: they must steal a ROM module that contains the saved consciousness of one of Case's mentors, legendary cyber-cowboy McCoy Pauley, nicknamed "Dixie Flatline." Armitage needs Pauley's hacking expertise, and the ROM construct is stored in the corporate headquarters of media conglomerate Sense/Net. A street gang named the "Panther Moderns" is hired to create a simulated terrorist attack on Sense/Net. The diversion allows Molly to penetrate the building and steal Dixie's ROM.
Case and Molly continue to investigate Armitage, discovering his former identity of Colonel Willis Corto. Corto was a member of "Operation Screaming Fist," which planned on infiltrating and disrupting Soviet computer systems from ultralight aircraft dropped over Russia. The Russian military had learned of the idea and installed defenses to render the attack impossible, but the military went ahead with Screaming Fist, with a new secret purpose of testing these Russian defenses. As the Operation team attacked a Soviet computer center, EMP weapons shut down their computers and flight systems, and Corto and his men were targeted by Soviet laser defenses. He and a few survivors commandeered a Soviet military helicopter and escaped over the heavily guarded Finnish border. Everyone was killed except Corto, who was seriously wounded and heavily mutilated by Finnish defense forces attacking the helicopter as it landed. After some months in the hospital, Corto was visited by a Government military official and then medically rebuilt to be able to provide what he came to realize was fake testimony, designed to mislead the public and protect the military officers who had covered up knowledge of the EMP weapons. After the trials, Corto snapped, killing the Government official who had contacted him and then disappearing into the criminal underworld.
In Istanbul, the team recruits Peter Riviera, an artist, thief, and drug addict who is able to project detailed holographic illusions with the aid of sophisticated cybernetic implants. Although Riviera is a sociopath, Armitage coerces him into joining the team. The trail leads Case and Molly to Wintermute, a powerful artificial intelligence created by the Tessier-Ashpool family. The Tessier-Ashpools spend most of their inactive time in cryonic preservation in a labyrinthine mansion known as Villa Straylight, located at one end of Freeside, a cylindrical space habitat at L5, which functions primarily as a Las Vegas-style space resort for the wealthy.
Wintermute's nature is finally revealed – it is one-half of a super-AI entity planned by the family, although its exact purpose is unknown. The Turing Law Code governing AIs bans the construction of such entities; to get around this, it had to be built as two separate AIs. Wintermute (housed in a computer mainframe in Berne, Switzerland) was programmed by the Tessier-Ashpools with a need to merge with its other half, Neuromancer (whose physical mainframe is installed in Rio de Janeiro, Brazil). Unable to achieve this merger on its own, Wintermute recruited Armitage and his team to help complete the goal. Case is tasked with entering cyberspace to pierce the Turing-imposed software barriers using a powerful icebreaker program. At the same time, Riviera is to obtain the password to the Turing lock from Lady 3Jane Marie-France Tessier-Ashpool, an unfrozen daughter clone and the current CEO of the family's corporation, Tessier-Ashpool SA. Wintermute believes Riviera will pose an irresistible temptation to her, and that she will give him the password. The password must be spoken into an ornate computer terminal located in Villa Straylight, and entered simultaneously as Case pierces the software barriers in cyberspace – otherwise the Turing lock will remain intact.
Armitage's team attracts the attention of the Turing Police, whose job is to prevent AIs from exceeding their built-in limitations. As Molly and Riviera gain entrance to Villa Straylight, three officers arrest Case and take him into custody; Wintermute manipulates the orbital casino's security and maintenance systems and kills the officers, allowing Case to escape. The Armitage personality starts to disintegrate and revert to the Corto personality as he relives Screaming Fist. It is revealed that in the past, Wintermute had originally contacted Corto through a bedside computer during his convalescence, eventually convincing Corto that he was Armitage. Wintermute used him to persuade Case and Molly to help it merge with its twin AI, Neuromancer. Finally, Armitage becomes the shattered Corto again, but his newfound personality is short-lived, as he is killed when Wintermute ejects him through an airlock into space.
Inside Villa Straylight, Riviera meets Lady 3Jane and tries to stop the mission, helping Lady 3Jane and Hideo, her ninja bodyguard, to capture Molly. Worried about Molly and operating under orders from Wintermute, Case tracks her down with help from Maelcum, his Rastafarian pilot. Neuromancer attempts to trap Case within a cyber-construct where he finds the consciousness of Linda Lee, his girlfriend from Chiba City, who was murdered by one of Case's underworld contacts. Case manages to escape after Maelcum gives him an overdose of a drug that can bypass his augmented liver and pancreas. Then, with Wintermute guiding them, Case goes with Maelcum 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 blinds Hideo with a concentrated laser pulse from his projector implant, but flees when he learns that the ninja is just as adept without his sight. Molly then explains to Case that Riviera is doomed anyway, as he has been fatally poisoned by his drugs, which she had spiked. With Lady 3Jane in possession of the password, the team makes it to the computer terminal. Case enters cyberspace to guide the icebreaker to penetrate its target; Lady 3Jane is induced to give up her password, and the lock is opened. Wintermute unites with Neuromancer, fusing into a superconsciousness. The poison in Case's bloodstream is washed out, and he and Molly are profusely paid for their efforts, while Pauley's ROM construct is apparently erased, at his own request.
In the epilogue, Molly leaves Case. Case finds a new girlfriend, resumes his hacking work, and spends his earnings from the mission replacing his internal organs so that he can continue his previous drug use. Wintermute/Neuromancer contacts him, saying that it has become "the sum total of the works, the whole show," and has begun looking for other AIs like itself. Scanning old recorded transmissions from the 1970s, the super-AI finds an AI transmitting from the Alpha Centauri star system. In the matrix, Case hears inhuman laughter, a trait associated with Pauley during Case's work with his ROM construct, thus suggesting that Pauley was not erased after all, but instead worked out a side deal with Wintermute/Neuromancer to be freed from the construct so he could exist in the matrix.
In the end, while logged into the matrix, Case catches a glimpse of himself, his dead girlfriend Linda Lee, and Neuromancer. The implication of the sighting is that Neuromancer created a copy of Case's consciousness when it previously tried to trap him. The copy of Case's consciousness now exists with that of Linda's, in the matrix, where they are together forever.