Nathan Paetsch and Tony Lydman also scored for the Sabres (44-16-5), who also pounded the Leafs 6-1 here at Air Canada Centre on Tuesday.
Ryan Miller was outstanding in goal for Buffalo, stopping 26 shots.
Nikolai Antropov scored late for the Leafs (31-26-9), who remained 10th in the Eastern Conference, one point behind Montreal - who lost at Boston on Saturday. Toronto also remained two points behind the final playoff spot held by the defending Stanley Cup champion Carolina Hurricanes, who play at Atlanta on Sunday afternoon.
The Eastern Conference-leading Sabres have lost only once in regulation in their last 11 games (9-1-1) despite missing one third of their regular lineup through injury. But it speaks to the depth of the organization with callups such as Stafford, Clarke MacArthur and Michael Ryan stepping in and filling the void without any dropoff.
The loss spoiled the return of fan favourite Darcy Tucker, who hadn't played since Jan. 1, while recovering from hairline fractures in his left foot. Tucker played on a fourth line with Travis Green and Chad Kilger, but also reclaimed his regular spot on the power play.
Backup goalie J.S. Aubin started his first game since Dec. 29, ending Andrew Raycroft's consecutive streak of starts at 26.
Lydman opened the scoring 4:52 in the second period after an evenly played opening 20 minutes, his point shot deflecting off a Leaf body and past a screened Aubin.
It was 2-0 after Drew Stafford, on a power play, deftly tipped a pass behind Aubin with 2:07 left in the middle period.
Paetsch put the result out of doubt with 3:42 left in the third period when he beat Aubin from the slot with a wrist shot. Antropov picked up his 12th of the season just 32 seconds later, but it was too little too late.
The Sabres went 1-for-5 on the power play, while Toronto was 0-for-6.
Notes: With both top defencemen Tomas Kaberle and Pavel Kubina sidelined, tough guy Wade Belak reverted to defence ... The return of Tucker sent Boyd Devereaux to the press box as a healthy scratch ... The injury list is still deep for Buffalo. Forwards Chris Drury, Maxim Afinogenov, Ales Kotalik, Daniel Paille, Andrew Peters, Paul Gaustad, Tim Connolly and defenceman Jaroslav Spacek are all out ... The Leafs host Washington on Tuesday before playing Ottawa in a home-and-home Thursday and Saturday.