Zach Smith and Jim O'Brien scored for the Senators, who did not dress Jason Spezza, Bobby Ryan and Erik Karlsson in the first of three games in three nights.
James van Riemsdyk and Dion Phaneuf scored for Toronto in a game tied 1-1 going into the final period. The Leafs almost tied it up in the dying seconds with a wild flurry and goalie James Reimer on the bench.
Reimer had 34 saves, while Robin Lehner made 26 stops for Ottawa.
The Senators outshot the Leafs 37-28.
The game was the first for Toronto since Sunday's brawl with Buffalo, which resulted in suspensions for the Maple Leafs' David Clarkson and Phil Kessel and a fine for Sabres coach Ron Rolston.