William Blake, an accountant hailing from Cleveland, Ohio, embarks on a journey by train to the frontier town of Machine, where he is to start a new accounting job at the local metalworks. However, during his trip, the train fireman eerily advises Blake against taking up the role. Upon his arrival, Blake is met with palpable hostility from the townspeople and soon discovers that the position he was promised has already been filled. The menacing John Dickinson, the owner of the company, forcefully drives Blake away at gunpoint, leaving him jobless and devoid of any means.
In his despair, Blake encounters Thel Russell, a former prostitute who makes a living selling paper flowers. He allows her to take him home, seeking comfort in her company. However, their brief moment of solace is shattered when Thel's ex-boyfriend Charlie unexpectedly appears, and in a violent confrontation, accidentally kills Thel as she attempts to protect Blake. The chaos culminates with Blake defending himself, killing Charlie with Thel’s gun before making a daring escape on Charlie’s horse. Unbeknownst to Blake, Dickinson is Charlie's father, and he soon hires a trio of lethal bounty hunters: Cole Wilson, Conway Twill, and Johnny "The Kid" Pickett, to track Blake down and bring him back, dead or alive.
After fleeing, Blake regains consciousness to find a large Native American man named Nobody attending to him, attempting to remove a bullet lodged near his heart. Unable to aid him, Nobody reveals that Blake is essentially a walking dead man. Upon discovering Blake's full name, Nobody becomes convinced that Blake is the reincarnation of the poet William Blake, a figure he reveres, despite Blake's ignorance of the poet himself. Seeing himself in Blake's plight, Nobody decides to accompany him on a journey towards the Pacific Ocean, intending to assist him in embracing his impending death.
As they venture westward, they leave a grim trail, accumulating notoriety reflected in the increasing bounties placed on Blake. Nobody decides that it is time for Blake to undergo a vision quest, and thus leaves him in the wilderness to confront his inner demons. During this quest, Blake faces perilous encounters, including killing two U.S. Marshals and experiencing haunting visions of nature spirits, all while mourning a fawn tragically killed by his pursuers. As he paints his face with the fawn's blood, he reconnects with Nobody.
Their journey brings them to a trading post where a prejudiced missionary attempts to end Blake's life but instead meets his own demise at Blake's hands. Shortly after, Blake suffers further injury, prompting Nobody to rush him towards a nearby Makah village for aid. In an emotionally charged moment, the villagers witness Blake's torment, leading to a poignant collapse from his injuries.
He later awakens in a canoe draped in a Native American funeral shawl. With heartfelt sorrow, Nobody bids Blake farewell and sends him out to sea. As Blake floats away, he witnesses a fatal confrontation between Nobody and Cole Wilson, powerless to intervene as he succumbs to his injuries. In his final moments, Blake gazes skyward, finding solace in the great beyond as his canoe drifts further into the ocean, marking the end of his tumultuous journey.
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