Other multiple honorees at Spike TV's eighth annual event were BioWare/Electronic Arts' "Mass Effect 2," which won best Xbox 360 game and two other prizes; and Sony's "God of War III," whose two prizes included best PlayStation 3 game.
Additional major winners included Nintendo's "Super Mario Galaxy 2," best Wii game; Activision Blizzard's "StarCraft II: Wings of Liberty," best PC game; and Sony's "God of War: Ghost of Sparta," best handheld game.
Spike's award show has become a high-profile showcase for forthcoming video games. This year's broadcast featured debut trailers for BioWare's "Mass Effect 3," Warner Bros.' "Batman: Arkham City," and Sony's "Uncharted 3: Drake's Deception."
The program was hosted by Neil Patrick Harris, who won the "best performance by a human male" VGA for providing the voice of Peter Parker and Spider-Man in Activision's "Spider-Man: Shattered Dimensions."
Besides taking home the big prize, "Red Dead Redemption" - from the studio behind the controversial "Grand Theft Auto" series - also won VGAs for best song, best original score and best downloadable content.