Fleury turned aside all 24 Sabres shots for the Pens, who rebounded from a shutout loss at Dallas Saturday.
Deryk Engelland, Tanner Glass and Chris Kunitz each scored as Pittsburgh recorded a fifth win in seven games overall.
Ryan Miller stopped 31-of-34 shots for Buffalo, losers of six in seven.
2014 amfAR Inspiration Gala [PHOTOS]
Julius Randle breaks leg during NBA debut