The friends tried their hands at the Ante Up For Africa poker event at the Rio Hotel, which raised money for the Enough Project and the International Rescue Committee, both aiding survivors of the crisis in Darfur.
Damon, 36, was knocked out within the first five minutes of the tournament – though he was leading the hand until he lost on the final card to a professional poker player.
Before the event, he talked about portraying an embattled poker player in the 1998 movie Rounders, which has been credited with helping to start the current poker phenomenon.
"I'm responsible for all these degenerates," Damon quipped. "It was much more of a subculture when I researched the movie. We had to get buzzed into places and go in these secret doors. It was much less mainstream."
Affleck, 34, no stranger to poker, faired better than his friend. He finished in the middle of the pack, but lasted longer than the other celeb players, who included Adam Sandler, Kevin James, Ray Romano, Brad Garrett, Montel Williams, Martin Sheen and Shannon Elizabeth.
Jae C. Hong / AP
Ante Up For Africa was co-organized by Damon's Ocean's Thirteen costar Don Cheadle and professional poker player Annie Duke, who has coached both Affleck and Damon.
"Hopefully we won't be here in five years for Darfur," Cheadle said at a press conference. "This isn't going to be solved one nation at a time. We need to bring this to the world. We're actually doing a great job in this country."