William Blake, 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 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 John Dickinson, the ferocious owner of the company, drives Blake from the workplace at gunpoint.
Jobless and without money or prospects, Blake meets Thel Russell, a former prostitute who sells paper flowers. He lets her take him home. Thel's ex-boyfriend Charlie surprises them in bed, shoots at Blake, and accidentally kills Thel when she shields Blake with her body. The bullet passes through Thel and wounds Blake, who kills Charlie with Thel's gun before climbing out the window and fleeing the town on Charlie's horse. Company owner Dickinson is Charlie's father and hires three 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 trying 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, rendering Blake 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.[6] He decides to care for Blake and to use Native methods to help ease him into death.
Blake learns of Nobody's past, marked by prejudice from Euro-Americans who objected to his Indigenous ancestry, and equally from Native Americans who objected that his mother and father were from two opposing tribes, Piikáni and Apsáalooke, respectively.[7] As a child, English soldiers abducted and brought him 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. They thus dub him Xebeche: "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 growing 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 his pursuers accidentally kill. He paints his face with the fawn's blood and rejoins Nobody. 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 instead dies at Blake's hands. Shortly after, Blake is shot again, and his condition rapidly deteriorates. Nobody hurries to take him by the river to a Makah village and persuades 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 a 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. Too weak to cry out, he can only watch as the two shoot and kill each other. Looking up at the sky one last time, Blake dies as his canoe drifts out to sea.
