In the game the Pretty Woman star described as being "like the comedy version of Fifty Shades of Grey," contestants are supposed to throw inflatable balls at each other's faces and later watch a slow-motion clip of their reaction.
"You didn't have to throw it so hard!" Fallon, 39, said after Roberts got him the first time.
The host later admitted he felt bad playing Face Balls with the actress because she is "America's Sweethart," but went ahead and threw the ball anyway.
After two rounds, it was clear who the winner was.
"I think I'm better handling big balls," Roberts proclaimed after her last throw.
The 46-year-old actress last starred in HBO's drama The Normal Heart alongside Mark Ruffalo and Matt Bomer.