The 28-year-old singer-actress had 10 nominations coming into the awards show, including album of the year for "I Am ... Sasha Fierce", song of the year for "Single Ladies" and record of the year for "Halo".
"Single Ladies" won song of the year and best R&B song. Beyonce also won best contemporary R&B album, best R&B female vocal for "Single Ladies" and best traditional R&B performance for "At Last", which she performed at President Barack Obama's inauguration.
The televised show started with Lady Gaga singing her hit "Poker Face", which won the award for best dance recording, while her album "The Fame" was named best electronic/dance album.
The Kings of Leon won best rock song and best rock group performance for "Use Somebody", beating out the likes of Bruce Springsteen, U2, Pearl Jam and Green Day.