The Penguins scored three times in the second period and held a 4-2 lead after two despite being outshot 25-11.
Overall, Ottawa held an 33-28 lead in shots but goalie Matt Murray helped the Penguins with his 30 saves.
Sidney Crosby scored his 400th goal in Sunday's game and had three assists -- one on each of the Aston-Reese goals.
Pittsburgh now has won a season-best nine straight games at home.
This was the first time Ottawa returned to Pittsburgh since the Penguins scored a double-overtime victory in Game 7 of last year's Eastern Conference finals.
Pittsburgh took a 1-0 lead on a Guentzel power-play goal 4:07 into the game when he redirected a Justin Schultz shot into the net.
The Senators tied it on Derick Brassard's goal 4:18 into the second period. However, the Penguins then scored three in a row over a stretch of 6:12 for a 4-1 lead.
Guentzel started everything 52 seconds after the Ottawa goal when he put away the rebound of a Phil Kessel shot. Malkin made it 3-1 at 10:01 with an assist from Carl Hagelin.
Malkin took a behind-the-back pass from Hagelin to the right of goalie Mike Condon and then wheeled around and put a backhander in on the short side.
Aston-Reese was playing in his fifth NHL game, and he scored his first goal to stretch the lead to 4-1 just 1:21 later after a Crosby assist.
Craig Anderson then replaced Condon, who allowed the four goals on only nine shots. Colin White scored for Ottawa later in the period before Letang scored his goal in the third period.
Matt Duchene scored for the Senators with 5:39 to go in the third period. Aston-Reese finished the scoring with an empty-net goal.
--Field Level Media