- Johnny Depp as William Blake, a meek accountant from Cleveland, Ohio
- Gary Farmer as Nobody, a strong and opinionated Native American forcibly raised by whites and later given the mocking name Xebeche, or "He Who Talks Loud, Saying Nothing", by fellow natives
- Crispin Glover as Train Fireman, a coal-covered boilerman who welcomes Blake to the "hell" of Machine
- Lance Henriksen as Cole Wilson, an infamous bounty hunter and murderous cannibal
- Michael Wincott as Conway Twill, a talkative bounty hunter
- Eugene Byrd as Johnny "The Kid" Pickett, a young bounty hunter
- John Hurt as John Scholfield, the business manager of Dickinson's factory
- Robert Mitchum as John Dickinson, a shotgun-toting industrialist in Machine
- Iggy Pop as Salvatore "Sally" Jenko, a cross-dressing, Bible-reading fur trader at a campsite
- Gabriel Byrne as Charlie Dickinson, Thel's ex-boyfriend and John Dickinson's son
- Jared Harris as Benmont Tench, a knife-toting fur trader at Sally's campsite
- Mili Avital as Thel Russell, a former prostitute who makes and sells paper flowers
- Billy Bob Thornton as Big George Drakoulias, a mountain man at Sally's campsite
- Michelle Thrush as Nobody's girlfriend
- Gibby Haynes as Man with gun in alley
- Alfred Molina as Trading Post Missionary, a corrupt missionary and businessman
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