Derek Roy assisted on all of Stafford's goals, and Ryan Miller made 32 saves for the Sabres, who won for the first time in four meetings with the Bruins.
Stafford, Tim Connolly and Rob Niedermayer all returned for Buffalo after being sidelined because of injuries. Stafford missed all but one of 16 games because of a shoulder injury. Connolly (groin) and Niedermayer (knee) were out the past eight games.
David Krejci and Michael Ryder scored, and backup goalie Tuukka Rask finished with 32 saves for Boston, which has lost two straight.
Miller made his eighth consecutive start after missing two because of groin soreness. He improved to 5-2-1 during that span.
Rask made his second start in seven games in relief of Tim Thomas, who will likely start on Thursday at Montreal.
Stafford completed his hat trick with 9:05 left to give the Sabres a 3-2 lift. In the left circle, he swatted in Roy's pass from the slot on the power play.
Ryder gave the Bruins a short-lived 2-1 advantage with his ninth of the season on the power play 6:21 into the third. After picking up the puck in the neutral zone, he split Steve Montador and Jochen Hecht, deked Miller, and slid in a shot.
But Stafford tied it 32 seconds later with his second of the game. In the slot, he one-timed Roy's pass from the right circle past Rask.
Krejci opened the scoring with his fifth of the season with 2:31 left in the first period. From the low slot he redirected defenseman Dennis Seidenberg's pass from the left point.
Stafford tied it with a power-play goal with 79 seconds remaining in the first. After Roy's rebound attempt went off the post, Stafford chipped in the puck on the backhand.
NOTES
Boston rookie C Tyler Seguin missed the game because of the flu. … Buffalo D Shaone Morrisonn missed his fourth game because of a concussion. … Boston RW Mark Recchi played in his 1,600th game, becoming the ninth NHL player to reach the milestone. … The Bruins are 6-3 in their last nine against the Sabres. … The Bruins are in the midst of an eight-game stretch in which they will play only two road games on the road. … The Sabres are 10-3-2 against backup goalies and 3-11-2 in games in which they faced the starter. Two of those wins came in shootouts.