Bill Guerin gave the Penguins the lead for good with 9:08 to play in the second, scoring on the power play. Fleury took over from there and won for just the second time in eight appearances.
Fleury's biggest save came on a breakaway by Nigel Dawes while Pittsburgh was protecting a one-goal lead early in the third.
Sidney Crosby produced his 30th goal of the season in the first period and Tyler Kennedy added a score in the third, bringing Pittsburgh its second win in three games.
Miikka Kiprusoff made 24 saves in the loss. It was Pittsburgh's third straight victory in Calgary.