The struggling Senators, who had won just one of their last six games and scored just nine goals in that stretch to fall to seventh place, remained two points ahead of the Buffalo Sabres in the final playoff position.
The loss was just the second for the Penguins in their last 15 games and their first in regulation since February 19.
Senators captain Daniel Alfredsson led the offensive outburst with two goals and two assists, including a shorthanded marker late in the second period to restore the Senators two-goal lead heading into the final period.
"We just kept working and plugging away," the Swede said. "It seemed like we got some momentum and getting some help from our special teams was huge."
The two-goal lead proved important as Sidney Crosby scored his first goal since returning to the Penguins lineup on March 15th to draw the Penguins to within one goal with eight minutes left.
"It's always nice to score, but we play to win," Crosby said. "It doesn't change a thing."
The Senators, however, put the game out of reach with three unanswered goals against Penguins backup goalie Brad Thiessen, who suffered his first defeat in his fourth NHL start.
"We didn't give (Thiessen) much help," Crosby said. "We made some big mistakes and didn't give him a chance. We have to regroup and get back right at it tomorrow."
Milan Michalek, Sergei Gonchar, Chris Phillips, Kyle Turris, Jason Spezza and Colin Greening also scored for the Senators while Matt Cooke scored twice for the Penguins and Tyler Kennedy added one.
Senators starting goalie Ben Bishop went down awkwardly on his knee while covering a loose puck in the crease during a Penguins powerplay midway through the second period and had to leave the game.
Craig Anderson came on in relief and allowed one goal on 20 shots.