On his game-winning goal, Comrie slipped the puck just inside the left post, past Pittsburgh netminder Marc-Andre Fleury.
The contest went to overtime when Chris Phillips' sixth goal this season led to a 3-3 tie at 13:54 of the third period. The goal came about two minutes after Nick Foligno's 14th had drawn Ottawa with 3-2.
Also in regulation, Chris Campoli scored his ninth. Netminder Brian Elliott was credited with 27 saves on 30 shots for the Senators, who have won five of their last six games.
Pittsburgh's Eric Godard, Tyler Kennedy and Sidney Crosby all scored once in regulation. In the shootout, won 2-1 by Ottawa, Crosby, the fifth shooter, scored Pittsburgh's only goal.
Fleury made 36 saves on 39 shots for the Penguins, who were playing in their fourth straight shootout.