Kyle Okposo, Michael Grabner and David Ullstrom scored for the Islanders, who snapped a 13-game losing streak in Pittsburgh.
Evgeni Nabokov started in goal and earned the victory with 30 saves on 32 shots. He left the game at the end of two periods with a lower body injury and was replaced by Al Montoya, who made 21 saves in the final frame.
The Penguins suffered only their second regulation-time loss in 17 games.
Pittsburgh goalie Marc-Andre Fleury was lifted after two periods, during which managed only 13 saves on 18 shots. Brad Thiessen relieved and stopped seven shots in the third.