The film begins as William Blake, played by Johnny Depp, sits in the carriage of a train heading through the American West during the pioneer era of the late 19th century. Hailing from Cleveland, Ohio Blake was offered work as an accountant in the booming resource town of Machine. As he nervously reads a magazine, he is approached by a coal shoveller who works on the train. The smoke-stained man begins to probe Blake about his reasons for heading to the frontier. In a blatant foreshadow, the man compares Machine and the American West to Hell. The train lurches to a stop and men begin to shoot buffalo from the windows of the train. This is Blake's first introduction to the violence of the setting he has entered.
After arriving in Machine, Blake walks down the Main Street. Like the coal shoveller suggested, the town is a rendering of Hell. The air is thick with industrial smoke, it is noisy and everyone appears menacing. When Blake arrives at the factory in which he is supposed to work the owner, John Dickinson, informs Blake that his position was filled a month ago. Blake wanders off and begins to drink in a bar. There he meets Thel Russell, a beautiful young woman. The two return to her home and make love. As they cuddle afterwards, a man barges into her room. Revealed to be Thel's ex-boyfriend, the man grows irate. He shoots Thel and Blake returns fire, killing the man. Blake, pierced by a bullet, stumbles out the window, steals a horse and leaves the town.
The film returns to the Machine factory owner, John Dickinson. He discovers that his son, Thel's ex-boyfriend, was murdered and that Blake is the culprit. He assembles three contract killers: the talkative Conway Twill, the cannibalistic Cole Wilson, and the young Johnny Pickett. The three quarrelsome men leave Machine to track down Blake.
Blake wakes up from his fugitive sleep as a Native American man kneels over him. The large man is using a knife and trying to remove the bullet from Blake's chest. Blake is alarmed but the man calms him. He informs Blake that removing the bullet would puncture his heart, and therefore Blake now exists in the liminal state between life and death. He is, in effect, the "dead man" of the film's title. The two men introduce one another. The Native American man tells Blake that his name is Nobody, and begins to retell his life story. Outcast as the child of two warring tribes, Blake was then captured by English settlers. He was forcibly transported to England where he was formally educated in English. Eventually he escaped and fought his way back to North America. When he arrived, however, his tribesmen refused to accept him. Like Blake, he accepts in a liminal space between his Native American identity, and his white settler upbringing. When Blake reveals his name, Nobody believes that he is the legendary English poet, William Blake.
Nobody tells Blake that it is his duty to lead Blake to the spirit world. Though Blake is confused, he is without any other options, and continues to follow Nobody. After the two men travel for several days, Nobody informs Blake that he is ready for a traditional Native American vision quest. He abandons Blake in the forest, and it is suggested that Blake ingests a hallucinogenic substance. His perspective radically alters. He begins to notice the tall trees and the wilderness. When he stumbles upon a dead deer, he symbolically marks his transition by marking his face with the animal's blood.
Meanwhile, the contract killers follow Blake's trail. After Johnny Pickett starts a fight with Cole Wilson, the latter shoots Pickett in the back of the head, leaving him to die on the bank of a river. Though it is not depicted, Wilson also kills Twill and is shown eating his hand.
Wandering in the forest, Blake stumbles upon Nobody having sexual relations with his girlfriend. The woman flees but Nobody remains with Blake. The two continue their journey. The men stumble on a campground where three pioneers sit around a fire. When Blake approaches them, it is suggested that they will rape him, though Nobody intervenes and the three men are killed. Along their travels, Nobody and Blake see wanted posters with rewards for Blake's capture. When they are retrieving supplies at a trading post, a priest notices Blake's comparison to the posters. He attempts to capture Blake but is shot and killed. In the scuffle, Blake is shot a second time. He grows delirious and Nobody hastens their voyage.
Riding in a stolen canoe, the men arrive at a Native American village. Nobody props the gravely wounded Blake as he stumbles through the settlement. He is in awe of the spiritual art and the totem poles, which stand in stark contrast to the town of Machine. The men retreat into a longhouse. When they emerge, a funeral canoe has been prepared for Blake. In this vessel he will transcend to the spiritual plane of Native American spirituality. Nobody pushes the semi-conscious Blake towards the ocean. When they arrive at the shoreline, Nobody leaves Blake as he is swept out into the water. As Blake looks up, he sees Nobody and Cole Wilson exchange in gunfire. Both men fall to the ground and die. Blake then dies. A distance shot shows the canoe being pulled out into the waves and the film ends.
