The Bethesda Softworks title beat Batman: Arkham City, Portal 2, Uncharted 3: Drake's Deception and The Legend of Zelda: Skyward Sword to the top prize.
Skyrim also claimed 'Best RPG' and helped Bethesda emerge victorious in the 'Studio of the Year' category.
The Legend of Zelda: Skyward Sword was another big winner on the night, earning 'Best Wii Game' and 'Best motion-Sensing Game'. Series creator Shigeru Miyamoto was also handed a 'Video Game Hall of Fame' prize.
Other winners included Uncharted 3 for 'Best Graphics', Batman Arkham City for 'Best Character of the Year' (the Joker), 'Best Xbox 360 Game' and 'Best Action-Adventure Game'. Portal 2 picked up for 'Best PC Game', 'Best Multiplayer', 'Best Performance by a Human Female' and 'Best DLC'.
This year's VGAs ceremony was broadcast live from Sony Studios in Los Angeles.
The winners in full:
Game of the Year: The Elder Scrolls V: Skyrim
Studio of the Year: Bethesda Softworks
Best Xbox 360 Game: Batman: Arkham City
Best PS3 Game: Uncharted 3
Best Wii Game: The Legend of Zelda: Skyward Sword
Best PC Game: Portal 2
Best Handheld / Mobile Game: Super Mario 3D Land
Best Shooter: Call of Duty: Modern Warfare 3
Best Action / Adventure Game: Batman: Arkham City
Best RPG: The Elder Scrolls V: Skyrim
Best Multi-Player: Portal 2
Best Individual Sports Game: Fight Night Champion
Best Team Sports Game: NBA 2K12
Best Driving Game: Forza Motorsport 4
Best Fighting Game: Mortal Kombat
Best Motion Game: The Legend of Zelda: Skyward Sword
Best Independent game: Minecraft
Best Adapted Video Game: Batman: Arkham City
Best Song in a Game: 'Build That Wall (Zia's Theme') by Darren Korb - Bastion
Best Original Score: Bastion
Best Graphics: Uncharted 3: Drake's Deception
Best Performance by a Human Male: Stephen Merchant as Wheatley - Portal 2
Best Performance by a Human Female: Ellen McClain as GLaDOS
Best Downloadable Game: Bastion
Best DLC: Portal 2 Peer Review
Video Game Hall of Fame: Shigeru Miyamoto
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