Claude Giroux had a goal and an assist for Philadelphia (30-26-7), which has won four of its past six games and is 14-3-1 in its past 18. Brian Elliott made 34 saves to win his second straight start.
The Flyers are seven points behind the Pittsburgh Penguins for the second wild card into the Stanley Cup Playoffs from the Eastern Conference.
WATCH: [All Sabres vs. Flyers highlights]
It was Philadelphia's first game since a 4-3 overtime win against Pittsburgh in the 2019 Coors Light NHL Stadium Series on Saturday.
"That was a big win for us Saturday night," said Elliott, who made 40 saves against the Penguins in his first start since sustaining a lower-body injury Nov. 15. "With the spectacle of the game, we know that this game is just as important. We came out and scored a couple quick ones, and I think that set the tone for the game. We went from there."
Jack Eichel and Casey Mittelstadt scored for Buffalo (29-26-8), which was coming of a 5-3 loss to the Toronto Maple Leafs on Monday and is 1-5-1 in its past seven games. Carter Hutton made 40 saves.
The Sabres are eight points behind the Penguins.
"I think it's just disappointing because it's a game of mistakes, and right now we're making more mistakes than the other team," Buffalo coach Phil Housley said.
Elliott was eased back from his injury, playing two games during a conditioning stint with Lehigh Valley of the American Hockey League, and then relieving Carter Hart in games against the Tampa Bay Lightning on Feb. 19 and the Montreal Canadiens on Feb. 21. He allowed three goals on 54 shots in the two relief appearances.