Pittsburgh took a 3-0 lead into the second period and wound up losing at home in a confrontation of teams that produced 100-point seasons.
Danny Briere began the Philadelphia rally by scoring 6:22 into the second period and 9:17 into the third.
With Pittsburgh's Brooks Orpik in the penalty box for interference, Brayden Schenn tied the score with 7:37 left in regulation.
Since Pittsburgh began playing in its new building, the Penguins have lost six of their seven home-ice games against the Flyers.
Pittsburgh will host Game 2 of the best-of-seven series Friday.
Sidney Crosby, Tyler Kennedy and Pascal Dupuis all scored for the Penguins in the first period, but Ilya Bryzgalov was perfect the rest of the way while making 25 saves. Bryzgalov evened his playoff record at 13-13 after suffering four losses in as many appearances last year.
Marc-Andre Fleury gave up the four goals on 26 shots.