- Joaquin Phoenix Larry 'Doc' Sportello
- Josh Brolin Detective Christian F. 'Bigfoot' Bjornsen
- Owen Wilson Coy Harlingen
- Katherine Waterston Shasta Fay Hepworth
- Reese Witherspoon Penny Kimball
- Benicio Del Toro Sauncho Smilax
- Martin Short Dr. Rudy Blatnoyd
- Jena Malone Hope Harlingen
- Joanna Newsom Sortilège
- Eric Roberts Michael Z. Wolfmann
- Hong Chau Jade
- Maya Rudolph Petunia Leeway
- Sasha Pieterse Japonica Fenway
- Michael Kenneth Williams Tariq Khalil
- Jeannie Berlin Tía Reet
- Sam Jaeger Agente Flatweed
- Jillian Bell Chlorinda
- Jefferson Mays Dr. Threeply
- Serena Scott Thomas Sloane Wolfmann
- Peter McRobbie Adrian Prussia
- Anders Holm
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