The New Orleans Saints quarterback carried home four trophies on the evening, including male athlete of the year, concluding a banner campaign for the humble star. His team also won an ESPY for best championship performance for their victory over the Indianapolis Colts in Super Bowl XLIV.
Brees was chosen male athlete over Kobe Bryant, LeBron James, Jimmie Johnson and Albert Pujols. All but James picked up trophies in other categories.
"I'd also like to thank the Who Dat nation," Brees said. "We love you."
Gold medal-winning skier Lindsey Vonn won female athlete of the year honors during the show hosted by "Saturday Night Live" comic Seth Meyers that aired live on ESPN from the Nokia Theatre. She beat out Serena Williams and basketball players Maya Moore of Connecticut and Diana Taurasi of the Phoenix Mercury.
"This is coming from the fans," Vonn said backstage. "It's not basketball, tennis or golf. It's not as highly viewed as other sports. To win is a lot more than I expected."
Vonn was also chosen best female Olympian.
Landon Donovan, who electrified American audiences throughout Team USA's World Cup run, picked up three awards, including best moment for his dramatic game-winning goal against Algeria. He also won best MLS player and the performance under pressure award.
Two of the sports world's biggest stars were not in attendance, but that might have been for the best as they came in for some brutal heckling from Meyers.
Tiger Woods got an earful during the opening monologue.
"We all know which free agent is making the most money this summer — Elin Nordegren," he said, referring to the golfer's estranged wife.
"Everyone, give it up for Tiger Woods, if you haven't already," Meyers said, drawing one of his biggest laughs.
LeBron James was booed when a montage of male athlete nominees was shown. The NBA star continues to deal with the fallout from his controversial ESPN special last week in which he announced that he was leaving Cleveland as a free agent to join friends Dwyane Wade and Chris Bosh with the Miami Heat.
"Did it really need to be an hour?" Meyers said. "Somebody time me. Miami. How long did that take? A second."
Actors Steve Carell and Paul Rudd spoofed James' hour-long decision special on ESPN in a pre-taped bit that culminated in Carell announcing he had chosen to eat dinner at Outback instead of his longtime haunt Chili's.
Meyers closed the show by saying, "Stay tuned to ESPN for an encore presentation of LeBron James' 'The Decision.'"