After posting a convincing victory on Monday in New Jersey to tie the Devils for first place in the Atlantic Division, the Flyers faced a 2-0 deficit less than seven minutes into this game.
Philadelphia battled back and drew even six minutes into the second period, just 62 seconds before Maxim Afinogenov ended a 10-game goal drought with the eventual game-winner.
The victory was Ruff's 211th as Buffalo coach, passing the Scotty Bowman for first place in franchise history. Ruff already holds team marks for games coached and playoff wins.
Daniel Briere and defenseman James Patrick also scored for the Sabres, who snapped a four-game winless streak while extending their home winning streak over Philadelphia to four.
John LeClair and Tony Amonte tallied for the Flyers, who had their three-game winning streak ended and remained one road victory from tying the team record.