The Leafs (4-1-1) lost both defenceman Cody Franson and forward David Booth to injuries in the win while the Sabres (1-2-1) lost forwards Johan Larsson and Patrick Kaleta.
Jonathan Bernier made 36 saves for the win while Andrey Makarov stopped 26 shots for Buffalo.
Mikhail Grigorenko and Nicolas Deslauriers gave the Sabres a 2-0 second period lead.
Sunday marked the first time the Leafs top line of James van Riemsdyk, Phil Kessel and Tyler Bozak skated as a unit in the pre-season.
Kessel got Toronto on the board in the second period with his first of the pre-season.
Van Riemsdyk tied it 2-2 midway through the third with a power-play goal, putting home the rebound off a Kessel shot.
Franson appeared to injure his left leg after he was shoved from behind by Sabres forward Torrey Mitchell behind the Toronto net at 11:15 of the third. The Leafs defenceman had to be helped off the ice and did not return.
Toronto also announced that Booth suffered a lower body injury and would not return.
The Sabres opened the scoring, 25 seconds in to the second as Grigorenko knocked down a Cody Hodgson saucer pass and beat Bernier stick-side for his first of the pre-season on Buffalo's eighth shot of the night.
Moments later, a Korbinian Holzer turnover nearly gave the Sabres a 2-0 lead, but Bernier managed to smother the lose puck.
Deslauriers gave Buffalo a 2-0 lead at 9:24 of the second getting his stick on a Rasmus Ristolainen point shot.
Less than a minute later, Kessel got the Leafs on the board, beating Makarov with a wrist shot from the face-off dot.
Toronto had two chances to tie the game with less than two minutes remaining in the second. The first opportunity came when Holland beat Makarov, short side, with a shot from the faceoff circle, but hit the post.
Then with 57 seconds remaining, Bozak had a glorious chance from the face-off circle, but was robbed by the glove of Makarov.
After starting out slow and being out-shot 7-1 through the opening 10 minutes of the first, Toronto gained momentum following an excellent point-blank chance for Nazem Kadri.
Van Riemsdyk had two excellent chances three minutes later as he redirected a Bozak feed and then got his own rebound but was robbed by the right pad of Makarov.
With Mike Weber in the box for four minutes the Leafs had two chances.
Kessel hit the post from the top of the faceoff circle with a wrist shot.
Moments later, Jake Gardiner one-timed the faceoff win, but Makarov got his glove son it to keep it scoreless.
The Sabres lost a pair of bodies in the first when Kaleta took a Morgan Rielly slapshot to the face at 11:32 of the opening period.
Then with less than a minute remaining in the first, Larsson skated into the elbow of an unsuspecting Petter Granberg and headed for the dressing room early.
Neither player returned.
Notes: Leafs forward David Clarkson is scheduled to see a specialist Monday for his cheekbone injury suffered last Friday night in Buffalo. … Toronto defenceman Stephan Robidas (leg) has been cleared for contact and is targeting the pre-season finale Oct. 3 for his Leafs debut. … Blue liner Henrik Tallinder is awaiting further results on his dislocated shoulder suffered against the Buffalo Sabres Sept. 26.