The film about a pregnant African American teenager and her abusive mother won best feature, best director for Lee Daniels, best first screenplay for Geoffrey Fletcher, best female lead for Gabourey Sidibe and best supporting female for Mo'Nique.
"Precious" is nominated for Academy Awards in many of the same categories, with Mo'Nique considered the odds-on favorite to receive best supporting actress Sunday evening at the Kodak Theatre.
Mo'Nique's acceptance speech wasn't as emotional as some of her other winning speeches this awards season, but she did take a special moment to acknowledge her co-star Sidibe, telling her, "You are a special gift to the universe, baby."
Presenter Ben Stiller, noting the ceremony's late hour and the independent nature of the assembled crowd, brought half-naked porn stars onstage to writhe in sexual positions while he read the nominees for best film.
On Friday, best male lead went to Oscar nominee Jeff Bridges for his moving performance as a dissolute country singer in "Crazy Heart." The role has won Bridges numerous awards this season, including honors from the Golden Globes and Screen Actors Guild.
Bridges gave a rambling speech in which he thanked many people and told the crowd, " 'Crazy Heart' is a gem of an independent film."
"Crazy Heart," directed by Scott Cooper, also won the Spirit prize for best first feature. Robert Duvall, who came to the stage with Cooper, told the crowd that the latter hadn't directed so much as a high school play before this film. "But," Duvall added, "he does a great job."
Woody Harrelson, also an Oscar contender, won for supporting male for "The Messenger."
Screenplay honors went to Scott Neustadter and Michael H. Weber for "(500) Days of Summer." Roger Deakins received the cinematography award for "A Serious Man."
"An Education" won best foreign film, and "Anvil! The Story of Anvil" took documentary honors.
The John Cassavetes Award for best feature made under $500,000 went to Lynn Shelton, the writer-director-producer of "Humpday." Kyle Patrick Alvarez, director of "Easier With Practice," received the Acura Someone to Watch Award. Bill and Turner Ross, directors of the documentary "45365," received the Chaz & Roger Ebert Truer Than Fiction Award. And Karin Chien, producer of "The Exploding Girl" and "Santa Mesa," received the Piaget Producers Award.
The third annual Robert Altman Award, which is given to a film's director, casting director and ensemble cast, went to Joel and Ethan Coen's "A Serious Man."
In the past, many Spirit winners have gone on to win Academy Awards, including last year's best supporting actress, Penelope Cruz, for "Vicky Cristina Barcelona," and documentary winner "Man on Wire."
The Spirit Awards, which honor independent and original filmmaking, have traditionally been held on the Saturday afternoon before the Oscars in a tent on the beach in Santa Monica. But the show moved to Friday evening at L.A. Live this year in celebration of the awards' 25th anniversary.
British comedian Eddie Izzard was the host of the ceremony, which was telecast live on cable's Independent Film Channel.