Jeff Carter scored twice and Scott Hartnell added a goal, and the Flyers killed two-man advantages in the first and second periods to help preserve the win.
After starting the season 6-0-2, the slumping Sabres (9-7-3) dropped their fourth straight to fall to 1-5-1 in their last seven games.
Buffalo's Ryan Miller finished with 22 saves two nights after being pulled early in the third period in Boston after surrendering seven goals. He dropped to 5-1-1 in his last seven starts against the Flyers.
The Flyers were without former Sabres co-captain Daniel Briere. He missed his fourth consecutive game because of a groin injury.
Buffalo, meanwhile, sat defenseman Henrik Tallinder and forward Maxim Afinogenov in an effort to shake up its slump. Right wing Mark Mancari, the second-leading scorer in the AHL, was recalled from Portland and inserted into the lineup, while defenseman Nathan Paetsch played for just the fifth time.
Hartnell opened the scoring with just 58 seconds left in the first period. Coming out of the penalty box after serving a minor penalty, Hartnell accepted a long pass from Simon Gagne to go in alone on Miller. Hartnell made a quick move before lifting a backhander over Miller's left shoulder for his fifth of the season.
The Sabres thought they tied it with 14:20 to go in the third period when Drew Stafford redirected Derek Roy's pass in tight. But after a video review, the goal was disallowed because Biron was able to keep the puck out while lying on his back.
Two minutes later, Jason Pominville hit the side of a gaping net before Carter made Buffalo pay for the missed opportunities, beating Miller with a bouncing-puck wrist shot from the top of the right circle that made it 2-0 with 11:41 to go.
Carter capped the scoring with his team-leading 13th into an empty net with a minute left.
Notes: Briere, along with Chris Drury, co-captained Buffalo for two years starting in 2005. ... The Sabres began a season-high four-game homestand. ... Hartnell snapped a nine-game goal-less streak. ... Gagne has a point in every game but two this season. ... Buffalo drafted Biron in the first round of the 1995 draft. He's 3-2-1 against the Sabres. ... Buffalo has allowed eight consecutive goals over the past two games. ... Carter has three goals in his last four games.