Jack Eichel scored his second goal of the night midway through the third period as the last-place Buffalo Sabres snapped the Leafs' club-record home winning streak at 13 games with a 3-2 victory.
Casey Nelson had the other goal for Buffalo (24-40-12), which got 39 saves from Chad Johnson to end a four-game slide.
Patrick Marleau, with a goal and an assist, and Nazem Kadri replied for Toronto (45-24-7).
Frederik Andersen made 24 stops for the Leafs, who were also looking to set a franchise record for victories in a season with 46.