William Blake (Johnny Depp), an accountant from Cleveland, Ohio, rides by train to the frontier company town of Machine to take up a promised accounting job in the town’s metal works. During the trip, the train Fireman (Crispin Glover) warns Blake against the enterprise. Arriving in town, Blake notes the hostility of the townsfolk towards him. He then discovers that the position has already been filled, and he is driven from the workplace at gunpoint by John Dickinson, 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 surprises them in bed and shoots at Blake, accidentally killing Thel when she tries to shield Blake with her body. The bullet passes through Thel and wounds Blake, but he is able to kill Charlie using Thel’s gun before dazedly climbing out the window and fleeing the town on Charlie’s horse. Company-owner Dickinson is Charlie’s father, and he hires three legendary frontier killers, Cole Wilson, Conway Twill, and Johnny “The Kid” Pickett to bring Blake back ‘dead or alive’.
Blake awakens to find a large Native American man (Gary Farmer) attempting to dislodge the bullet from his chest. The man, calling himself Nobody, reveals that the bullet is too close to Blake’s heart to remove, and Blake is effectively a walking dead man. When he learns Blake’s full name, Nobody decides Blake is a reincarnation of William Blake, a poet whom he idolizes but of whom Blake is ignorant. He decides to care for Blake, and use Native methods to help ease him into death.
Blake learns of Nobody’s past, marked both by Native American and white racism; it is detailed that he is the product of lovers from two opposing tribes, and how as a child he was abducted by English soldiers and brought to Europe as a model savage. He was briefly educated before returning home, where his stories of the white man and his culture were laughed off by fellow Native Americans. He gained his name, Xebeche, at this point, the literal translation of which is revealed to be “He who talks loud, saying nothing”. Nobody resolves to escort Blake to the Pacific Ocean to return him to his proper place in the spirit-world.
Blake and Nobody travel west, leaving a trail of dead and encountering wanted posters announcing higher and higher bounties for Blake’s death or capture. Nobody leaves Blake alone in the wild when he decides Blake must undergo a vision quest. On his quest, Blake kills two U.S. Marshals, experiences visions of nature spirits, and grieves over the remains of a dead fawn that was killed accidentally by his pursuers. He paints his face with the fawn’s blood and rejoins Nobody on their journey. Meanwhile, the most ferocious member of the bounty hunter posse, Cole Wilson, has killed his comrades (eating one of them) and continued his hunt alone.
At a trading post, a bigoted missionary identifies Blake and attempts to kill him but is instead killed by Blake. Shortly after, Blake is shot again and his condition rapidly deteriorates. Nobody hurries to take him by river to a Makah village and convinces the tribe to give him a canoe for Blake’s ship burial. Delirious, Blake trudges through the village, where the people pity him, before he collapses from his injuries.
He awakens in a canoe on a beach wearing Native American funeral dress. Nobody bids Blake farewell and then pushes the canoe out to sea. As he floats away, Blake sees Cole approaching Nobody, but is too weak to cry out and can only watch as the two men shoot and kill each other. As he looks up at the sky one last time, Blake dies and his canoe drifts out into the sea. The film fades out with beams of sunlight in the clouds still visible, showing Blake is either in the Spirit World or has been reborn again.