William Blake (Johnny Depp), an accountant from Cleveland, Ohio, becomes mortally wounded and embarks on a bloody journey through a sordid depiction of the American Old West.

William Blake rides by train to the frontier company town of Machine to assume a promised job as a bookkeeper in the town's namesake metal works. During the trip, a Fireman (Crispin Glover) warns Blake against the enterprise while passengers shoot buffalo from the train windows. Arriving in town, Blake discovers that his position has already been filled, and is driven from the workplace at gunpoint by John Dickinson (Robert Mitchum), the ferocious owner of the company. Jobless and without money or prospects, Blake meets Thel Russell (Mili Avital), a former prostitute who sells paper flowers. He lets her take him home. Thel's ex-boyfriend Charlie (Gabriel Byrne) surprises them in bed and shoots Blake, accidentally killing Thel when she tries to shield Blake with her body. A wounded Blake shoots and kills Charlie with Thel's gun before climbing dazedly out the window and fleeing Machine on a stolen pinto. Company-owner Dickinson, the father of Charlie, hires three legendary frontier killers to hunt down Blake as the murderer of his son and Thel, although he seems to care most about recovering the stolen horse.

Blake awakens to find a large American Indian (Gary Farmer) attempting to dislodge the bullet from his chest. The Indian, calling himself Nobody, reveals that the bullet is too close to Blake's heart to remove, and Blake is effectively walking dead. When he learns Blake's full name, Nobody decides Blake is a reincarnation[4] of William Blake, a poet whom he idolizes but of whom accountant Blake himself is ignorant. Nobody resolves to escort Blake to the Pacific Ocean to return him to his proper place in the spirit-world. After discovering that Blake is being hunted, Nobody also determines to assist Blake in expanding his legend by killing as many more white men as may become