Scott Hartnell had a goal and three assists, Jakub Voracek notched a goal and an assist and Claude Giroux had five helpers for the Flyers, who scored seven unanswered goals to win for just the second time in seven games.
Ilya Bryzgalov, starting for the first time since February 7, made 27 saves to earn the victory.
"I think it's a win that happened at the right time," said Talbot. "We definitely need to build off this in the future."
The first period belonged to the Sabres. Pominville opened the scoring with his third goal in as many games, emerging from behind the net and slamming home a feed from Tyler Myers just 5:15 in.
Vanek made it 2-0 at the midway point with a low slap shot from the top of the right circle, which slipped under the right pad of Bryzgalov.
"In the first I think we had control," said Pominville. "We were doing some good things. We were generating chances, we weren't giving up much."
The rest of the game belonged to the Flyers. Talbot scored less than a minute into the second, redirecting a blue-line slap shot from Braydon Coburn past Enroth
Simmonds, who took a puck off the face in warmups and was a late arrival to the Flyers' bench, put his team on top with back-to-back power play tallies.
Donning a full face mask, Simmonds stopped a Giroux shot in front of the net, turned and fired it past Enroth for the equalizer at 3:32. Then, at 6:49, he was again camped in front, and buried a rebound of a Hartnell shot for the go- ahead score.
"That's coming right from the table and having your mouth numb like that and teeth knocked around and everything else," Flyers coach Peter Laviolette said of Simmonds. "He was ready from the start."
Erik Gustafsson extended the lead at the 13:48 mark, burying a drop pass from Voracek in front for his first NHL goal.
The Flyers put the game away in the third. Talbot drove home a deft centering feed from Eric Wellwood less than four minutes in, Voracek found the back of the net with a wrist shot seconds later and Hartnell's tip-in sealed the final margin at the midway point.
Bryzgalov stopped 17 shots over the final two periods.
Giroux notched the first five-point game of his career...The Flyers have won all three meetings between the teams this season...On Thursday, Philadelphia acquired defenseman Nicklas Grossman from the Dallas Stars in exchange for a 2012 second-round pick and a 2013 third-round pick.