The actors will appear on the Oct. 13 episode of the show.
"Sheldon makes Leonard choose -- their friendship or a party at Wil Wheaton's house. Tough one," said in a synopsis from CBS, which describes Wheaton as Sheldon's "old nemesis."
Johnny Galecki plays Leonard on the series. Jim Parsons won an Emmy Sunday for his portrayal of Sheldon on the sitcom about a pair of brilliant physicists whose lives are turned upside down when a free-spirited beauty, played by Kaley Cuoco, moves in next door.
Created by Chuck Lorre, the series is in its fifth season on CBS.