James also won in the championship performance and NBA player categories, completing a sweep of the three awards he won last year. He shared in the best team award Wednesday night.
James beat out Miguel Cabrera of the Detroit Tigers, Minnesota Vikings running back Adrian Peterson and Olympic swimmer Michael Phelps for male athlete honors.
Serena Williams won two awards, including female athlete of the year. She defeated a pair of Olympians, gymnast Gabby Douglas and swimmer Missy Franklin, and former Baylor basketball star Brittney Griner. Williams didn't attend because she's playing a tournament in Sweden.
Peterson and Phelps also won two awards each.
Jon Hamm, the star of AMC's "Mad Men" and a noted St. Louis Cardinals fan, hosted the 21st annual show from the Nokia Theatre.
Quarterback Johnny Manziel of Texas A&M won male college athlete honors after flying in earlier from Hoover, Ala., where he attended SEC media day. Griner, who now plays for the WNBA's Phoenix Mercury, won female college athlete.
Peterson won trophies for NFL player and best comeback, while Cabrera won as best MLB player.
Williams won female tennis player, giving her eight career ESPYs.
Phelps also claimed best male Olympian, while teenage swimming sensation Missy Franklin won best female Olympian.
San Francisco 49ers quarterback Colin Kaepernick won as breakthrough athlete. Rick Pitino won as coach-manager for guiding the Louisville Cardinals to a national basketball championship.
The best game was Game 6 of the NBA finals between the Heat and San Antonio Spurs.
The award for best upset went to Florida Gulf Coast's men's basketball team, a No. 15 seed that upset No. 2 seed Georgetown in the NCAA tournament.
The best moment award singled out 7-year-old Jack Hoffman's 69-yard touchdown run at Nebraska's spring game in April, which was replayed on national TV and viewed more than 2 million times on YouTube. The boy from Atkinson, Neb., has brain cancer.
Sidney Crosby won NHL player, while Thierry Henry of the New York Red Bulls won MLS player.
South Carolina football player Jadeveon Clowney won best play for his hit on Michigan's Vincent Smith in which he knocked the runner on his back with a helmet-toppling smack, then reached out with one hand to snare the ball.
The Arthur Ashe Courage award went to "Good Morning America" co-anchor Robin Roberts, who underwent a bone marrow transplant last fall to treat a life-threatening blood and bone marrow disease. She was off work for five months before returning to her TV job. James presented Roberts with the award, and first lady Michelle Obama saluted her via video.
The Jimmy V Award for Perseverance was given to father-and-son duo Dick and Rick Hoyt by actor-director Ben Affleck. The younger Hoyt was born with cerebral palsy and is unable to use his hands and legs. His 73-year-old father Dick pushes him in a custom-made running chair, and together they have participated in more than 1,000 endurance events, including 31 Boston Marathons.
The winners in most categories were determined by fan voting.