The hip-hop quartet was named favorite group twice, in the rap/hip hop and soul/rhythm & blues categories. They also won favorite rap/hip-hop album for "Monkey Business."
Expressing gratitude via satellite from Costa Rica, the band's frontman, will.i.am, thanked fans and artists "for keeping hip-hop progressive and pushing it forward."
Awards came in pairs for the Red Hot Chili Peppers, Kelly Clarkson, Mary J. Blige and Rascal Flatts.
The Red Hot Chili Peppers were favorite alternative artist and pop/rock band. They accepted their award via satellite from London, with bass player Flea beat-boxing as lead singer Anthony Kiedis thanked "the American people."
Clarkson captured trophies for pop/rock female and adult contemporary artist, categories presented before the televised presentations began in the performance-filled show. Rascal Flatts won favorite country group and the T-Mobile Text-In award, which is chosen by fans.
Blige won favorite soul/rhythm & blues album for "The Breakthrough." She was also the favorite female R&B artist. She accepted the award from surprise presenter Britney Spears, who looked sleek in a knee-length cream-colored frock and long blond hair.
Oscar winner Jamie Foxx was named favorite male soul/rhythm & blues artist.
"I'm like a rookie in this music thing," he said. "This means a lot more than you think, man."
Foxx wore a white tuxedo and sat behind a grand piano to perform "Wish U Were Here" from his 2005 album, "Unpredictable."
Nickelback took home the trophy for pop/rock album. Dancehall singer Sean Paul was named favorite male pop/rock artist.
Among country honors, favorite female artist went to Faith Hill, male artist went to Toby Keith and Tim McGraw's "Greatest Hits Volume 2" was favorite album. Country singer and "American Idol" winner Carrie Underwood was named favorite breakthrough artist.
Eminem was favorite male rap/hip-hop artist. Shakira won favorite Latin artist, and Kirk Franklin captured the award for contemporary inspirational music.
"I know that a lot of people that say that they're Christians you know, we don't always represent, and we don't always live it and we do sometimes some very stupid things, and you know we're not doing a good job," said Franklin, wearing blue jeans with a black velvet tuxedo jacket. "I want to make sure that when you see my life that it's a life that I'm gonna be proud of."
Television talk-show host Jimmy Kimmel kicked off the three-hour ceremony at the Shrine Auditorium, televised live on ABC, with a skit that placed a ringer for Spears' ex, Kevin Federline, into a wooden crate dumped into the ocean. Kimmel cracked that Federline was the world's first "no-hit wonder."
Beyonce began the show, belting out her single "Irreplaceable" while vamping around the stage in a sparkly sequined minidress. The Pussycat Dolls also chose sequins for their performance, while Nelly Furtado opted for a skin-tight white dress and stick-straight hair.
Gwen Stefani made a stylish return to the music scene, performing the single "Wind It Up" from her forthcoming album, "The Sweet Escape." The new mom, wearing a skimpy sequined shift and a shoulder-length platinum bob, yodeled and rapped convincingly throughout the tune, reports AP.
Not to be outdone, rapper Jay-Z stepped out of retirement and back into the spotlight, accompanied by scantily clad dancers as he performed the single "Show Me What You Got" from his new record, "Kingdom Come."
Lionel Richie made a festive return to the awards. Introduced by his diminutive daughter, Nicole Richie, the former Commodore performed a medley that included his '80s party anthem "All Night Long."
Barry Manilow performed a medley of favorites from his latest collection, "The Greatest Songs of the Sixties."
Some awards were announced off camera before the broadcast presentations.
The American Music Awards honor the best in pop/rock, country, soul/rhythm & blues, rap/hip hop, Latin, alternative, adult contemporary and contemporary inspirational music. Nominees were chosen based on record sales and winners were selected by a survey of about 20,000 listeners.