In a cross-genre category, country group Sugarland bested alternative rockers The Killers and singer Jesse McCartney for breakthrough new artist.
In awards presented off-camera, Green Day won favorite artist in the Alternative category and the band's album, American Idiot, received the pop-rock category honor.
Eminem won the favorite male artist in the rap/hip-hop division, while Clarkson received the honor for favorite artist in the adult contemporary category.
Nominees were chosen on the basis of record sales, with winners selected through a survey of about 20,000 listeners.
Comedian Cedric The Entertainer hosted the three-hour ceremony, broadcast live on ABC from the Shrine Auditorium in Los Angeles.
He took to the stage wearing a grey pinstripe suit and holding a boombox that he dubbed the first iPod. He quickly noted that new versions of Apple Computer Inc's digital music player seem to be coming out all the time and getting smaller and smaller.
``I got the new Apple Tic-Tac. It freshens your breath and plays one song,'' he joked.
The scene on the red carpet before the show reflected the hodgepodge of musical genres being honored at the AMAs, with hip-hop, pop and country stars making their way through the gantlet of press.
``It's an American quilt,'' said Lauper, who arrived in a black dress with sheer sleeves and a fringed hem.
She and McLachlan exchanged compliments backstage after the rousing response they received for their duet on Time After Time, which was co-written by Lauper.
``Time after Time is one of the best pop songs ever written, in my opinion. It's an incredible, beautiful, timeless song,'' McLachan said.
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