Rihanna won the top female artist award and Eminem won the top male artist award. Other award winners included Justin Bieber, Lady Antbellum and the Black Eyed Peas.
U2 was also honored for their blockbuster "360" tour as the top touring act of 2010, while Neil Diamond received Billboard' "Icon" award.
Beyonce received a special "Millennium" Award for her career achievements. She was lauded in a video by an array of legends and luminaries, including Stevie Wonder, Barbara Streisand, Bono, Lady Gaga and first lady Michelle Obama.
"This is a moment I have to soak in because it's going to be - and it is - one of the best moments of my life," Beyonce said in her speech.
Click here for a complete list of winners.
Beyonce also performed her new song, "Run the World (Girls)."
Other performances included Rihanna on "S&M" joined by Britney Spears, Lil Wayne with Mary J. Blige and Diamond leading the audience in a sing-a-long to "Sweet Caroline" and "America." Cee Lo Green performed as well -- on a flying, glittery piano.
The Billboard awards had been a staple since 1989, but gave out what appeared to be its last award in 2006. This year, the show was brought back.
The Billboard awards are given out to music's most popular artists. The finalists and winners are determined by their rank on the Billboard charts and their "social and streaming activity."
The Associated Press contributed to this report.
