Ryan Whitney, Jordan Staal, Evgeni Malkin and Dominic Moore scored Pittsburgh's goals. Derek Roy and Chris Drury replied for the Eastern Conference leaders, who lost a second consecutive game for only the second time this season.
NHL scoring leader Sydney Crosby of the Penguins picked up one assist.
Buffalo had a 33-27 shots advantage, but Fleury continued his hot streak. He's allowed only three goals in the last three games - all Pittsburgh wins.
Roy struck at 14:44 when he slammed home a Toni Lydman pass for the only goal of the first period.
In the second, Whitney and Drury exchanged power-play goals before Staal tied it at 13:39 by knocking in a rebound. Malkin put the Penguins up 3-2 on a power play at 19:57 when he slapped a rocket over goalie Ryan Miller's left shoulder for his 19th goal.
Moore completed the scoring by shooting into an empty net with 13 seconds left in the game.
Notes: The Sabres had their four-game, home-winning streak snapped . . . Sabres D Henrik Tallinder missed his first game because of an ankle sprain sustained in Wednesday's loss to Ottawa. He is expected to be out at least two weeks . . . Buffalo will play its third game in four nights Saturday in Toronto . . . Roy scored for the first time in 12 games . . . Crosby has seven points in three games . . . Pittsburgh converted two of three power-play attempts and is 8-for-26 with the man advantage the last four games.