The Sens (18-25-4) had goals from Zach Sanford, Austin Watson and Brady Tkachuk while Anton Forsberg stopped 23 shots. Craig Anderson made 25 saves while Kyle Okposo scored for Buffalo (16-25-8).
"Our penalty kill wins us the game tonight," Senators head coach D.J. Smith said. "The third period, just do it right for 20 minutes. We went to work in the offensive zone. We didn't have to defend a whole lot. We worked way harder offensively … and we got rewarded."
Knotted at 1-1 through 40 minutes, Ottawa took its first lead of the night at 10:49 of the third as Watson tipped home Nick Holden's point shot for his fourth of the season and what would be the eventual game-winner.
"It's nice when you get rewarded with a goal, especially late in a tight hockey game," Watson said.
The Sens shut the Sabres down in the third period as they managed just four shots in the third period and went a stretch of 22 minutes without forcing Forsberg into a save. Tkachuk sealed the deal with an empty-net goal with 17 seconds left.
"We had a game plan the whole game and we really got to it in the third period," Sanford said. "We were able to play our game."
The Senators took three penalties in the opening period and it finally caught up to them as at 13:37, Okposo skated in alone from the right wing off of Rasmus Asplund outlet pass and he deked Forsberg to bury his 11th of the campaign.
Ottawa found the tying goal at 16:04 of the second as Tyler Ennis, playing against the team that drafted him in the first round in 2008, fed Sanford, who had snuck in behind Henri Jokiharju, with a gorgeous pass through Rasmus Sandin and the Senators forward made no mistake by roofing the puck past Anderson as he came back across the crease for his eighth of the season.
All-in-all, the Sens killed off five of Buffalo's six power play. Nine of Forsberg's saves came while the Sens were down a man.
"Penalty killing starts with your goaltender," Watson said. "When your goaltender is making all of the saves it lends a lot of confidence to the killers in front of him."
With his assist, Ennis registered the 200th of his NHL career.
The Senators are back in action Saturday when they host Boston at 7 p.m.