Jared Cowen scored the game-winning goal 45 2, at First Niagara Center.
Jason Spezza brought the puck into the offensive zone on the left wing and flung it into the right corner for Erik Karlsson. Karlsson turned and found an unchecked Cowan, who buried it in behind Ryan Miller after sneaking in from his point position.
Milan Michalek and Peter Regin also scored, while Spezza ended his night with a pair of assists for the Senators, who snapped a six-game skid against the Sabres dating back to last season. Craig Anderson stopped 27 shots in the win.
Paul Szczechura and Tyler Ennis lit the lamp for the Sabres, who have lost two straight games. Miller made 41 saves in defeat.