The title took home five awards, including 'Game of the Year', 'Visual Art', 'Best Technology', 'Best Writing' and 'Best Audio'.
Other winners include Batman: Arkham Asylum for 'Best Game Design', Scribblenauts for 'Best Handheld' and 'Innovation', and Farmville for 'New Social/Online Game'.
Elsewhere, John Carmack was given a Lifetime Achievement Award, and Valve's Gabe Newell received the Pioneer Award.
The winners in full:
Game of the Year: Uncharted 2: Among Thieves
Best Game Design: Batman: Arkham Asylum
Best Handheld Game: Scribblenauts
Best Visual Art: Uncharted 2: Among Thieves
Best Technology: Uncharted 2: Among Thieves
Best Writing: Uncharted 2: Among Thieves
Best Audio: Uncharted 2: Among Thieves
Best Debut: Torchlight (Runic Games)
Best Downloadable Game:Flower
Best New Social/Online Game: Farmville
Lifetime Achievement Award: John Carmack, id Software
Pioneer Award: Gabe Newell, Valve Software