Dans la deuxième moitié du XIXe siècle, Bill Blake, jeune comptable en route pour le confins de l'Ouest américain, entreprend un voyage initiatique où il devient malgré lui un hors-la-loi traqué. Blessé, il est recueilli par Nobody, un Amérindien lettré rejeté des siens, qui l'identifie d'emblée à son homonyme défunt, le poète anglais William Blake, et décide de sauver son âme.
Dead Man is the story of a young man's journey, both physically and spiritually, into very unfamiliar terrain. William Blake is traveling to the extreme Western frontiers of America sometime in the 2nd half of the 19th century. Lost and badly wounded, he encounters a very odd, outcast Native American - named "Nobody" - who believes Blake is actually the dead English poet of the same name. The story, with Nobody's help, leads William Blake through situations that are in turn comical and violent. Contrary to his nature, circumstances transform Blake into a hunted outlaw, a killer, and a man whose physical existence is slowly slipping away. Thrown into a world that is cruel and chaotic, his eyes are opened to the fragility that defines the realm of the living. It is as though he passes through the surface of a mirror, and emerges into a previously-unknown world that exists on the other side.