| Joanna Newsom | ... | Sortilège |
| Katherine Waterston | ... | Shasta Fay Hepworth |
| Joaquin Phoenix | ... | Larry "Doc" Sportello |
| Jordan Christian Hearn | ... | Denis |
| Taylor Bonin | ... | Ensenada Slim |
| Jeannie Berlin | ... | Aunt Reet |
| Josh Brolin | ... | Lt. Det. Christian F. "Bigfoot" Bjornsen |
| Eric Roberts | ... | Michael Z. Wolfmann |
| Serena Scott Thomas | ... | Sloane Wolfmann |
| Maya Rudolph | ... | Petunia Leeway |
| Martin Dew | ... | Dr. Buddy Tubeside |
| Michael Kenneth Williams | ... | Tariq Khalil |
| Hong Chau | ... | Jade |
| Shannon Collis | ... | Bambi |
| Christopher Allen Nelson | ... | Glenn Charlock |
| Benicio Del Toro | ... | Sauncho Smilax, Esq |
| Catherine Haena Kim | ... | News Reporter |
| Jena Malone | ... | Hope Harlingen |
| Owen Wilson | ... | Coy Harlingen |
| Vivienne Khaledi | ... | Amethyst Harlingen |
| Yvette Yates | ... | Luz |
| Andrew Simpson | ... | Riggs Warbling |
| Joe Dioletto | ... | Cop with Bigfoot |
| Reese Witherspoon | ... | Deputy D.A. Penny Kimball |
| Sam Jaeger | ... | Agent Flatweed |
| Timothy Simons | ... | Agent Borderline |
| Jack Kelly | ... | Burke Stodger |
| Jillian Bell | ... | Chlorinda |
| Christian Williams | ... | Smedley |
| The Growlers | ... | The Boards |
| Belladonna | ... | Clancy Charlock (as Michelle Sinclair) |
| Alina Gatti | ... | Howdy Doper's Phone Voice (voice) |
| Elaine Tan | ... | Xandra |
| Martin Short | ... | Dr. Rudy Blatnoyd, D.D.S. |
| Sasha Pieterse | ... | Japonica Fenway |
| Wilson Bethel | ... | LAPD Officer #1 |
| Anders Holm | ... | LAPD Officer #2 |
| Emmet Unverzagt | ... | Bigfoot's Kid |
| Jefferson Mays | ... | Dr. Threeply |
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