The win avenges a 2-0 loss to Toronto on Tuesday and ends a three-game losing streak for the Sabres, who have won just three of their last 12 games to sit 19-19-5 for the season.
"It wasn't our best game, so it was nice to be able to get that one," Sabres captain Jason Pominville said.
"It was fun to see guys keep their composure. We're not going through the stretch we would want, but we were playing well."
Buffalo gained the early advantage with two goals on their first three shots against Toronto goalie Jonas Gustavsson, who earned a shutout on Tuesday.
Matt Ellis scored a minute into the game when his centering pass deflected off Maple Leafs defenseman Cody Franson. Paul Gaustad then doubled the lead three minutes later with a wrist shot from distance that Gustavsson probably should have saved.
The Maple Leafs got back on level terms late in the period with goals by Mikhail Grabovsky and Joey Crabb.
The Sabres scored the game-winner in the second period when Jason Pominville converted a beautiful pass from Thomas Vanek, who threaded the puck through two Maple Leafs defenders.
"I knew the whole time he (Vanek) was going to make the play," said Pominville. "It just landed right on my stick. I just had to settle it down and put it away. It was one of those plays not many guys can make."
Buffalo's penalty killers held off the Maple Leafs through four shorthanded situations and goalie Ryan Miller made 24 stops, nine of them in the final period, to help deliver the win.
"A couple of bad bounces early put us behind the eight-ball," Leafs captain Dion Phaneuf said. "We fought, we just didn't have enough to even it up in the third."