Drew Stafford scored twice, first on a penalty shot, and added an assist on Paul Gaustad's goal. Patrick Lalime stopped all 27 shots he faced in relief of starter Ryan Miller, who was pulled after allowing three goals on 11 shots through 22 minutes.
Stafford's sixth multigoal game snapped a 15-game goal drought two days after he was a healthy scratch in a 5-3 win at St. Louis.
Jordan Staal, Bill Guerin and Chris Kunitz scored for the Penguins, who squandered a three-goal lead for the first time since a 5-3 loss at Nashville last Jan. 8.
The Penguins dropped to 1-3 in their past four games, and blew a chance to move into a tie with New Jersey atop the Eastern Conference standings.
With 53 points, the Penguins are two back of New Jersey as they travel to face their Atlantic Division rival on Wednesday.
Stafford sparked the comeback by scoring twice in the second period and then made a great move to avoid two Penguins defenders and slip a pass through the crease to Gaustad, who tied the game at 3 at 7:28 of the third.
Pominville scored a power-play goal three minutes later converting a give-and-go with Tim Connolly. Feeding Connolly in the left corner, Pominville drove to the net, got the return pass and snapped a shot that beat Marc-Andre Fleury just inside the far post.
Buffalo hadn't overcome a three-goal deficit since a 5-4 shootout win at Dallas last Jan. 16.
After Staal and Guerin scored first-period goals, the Penguins appeared to take command 90 seconds into the second period when Kunitz, set up in the high slot by a smart pass from Sidney Crosby, blasted a 50-footer over Miller's left shoulder. The goal chased Miller, in a week in which he is expected to be named to U.S. Olympic team.
Miller then showed his frustration by throwing several pieces of equipment as he took his seat at the end of the bench.
Stafford was given a penalty shot 13 minutes into the second period following a scramble in front during which Penguins defenseman Jay McKee gathered the loose puck into his body while lying in the crease. Stafford drove in on net and then appeared to fan on his shot, but it fooled Fleury, who allowed it beat him through the legs.
Notes
The Penguins, who kicked off a four-game road trip, had their bus become stuck in the snow three blocks from the hotel. Coaches and team officials had to get out to push. … With 462 career wins with the Sabres, coach Lindy Ruff moved to within three of passing Glen Sather (Edmonton) for fourth place on the NHL list of coaching wins with one team. … Penguins D Mark Eaton returned after missing three games with a lower body injury.