The Flyers were held to two goals or fewer for the 18th time this season. They also has been blanked by Belfour each of the first two meetings with the Maple Leafs.
When Gagne netted his third goal in two games 7:10 into the third period, he ended Belfour's shutout streak against the Flyers at 195 minutes, 34 seconds.
"He definitely is a skilled player," Belfour said of Gagne. "He's real good on breakaways and he has a nice wrist shot."
"We had the energy through the whole game, but we had another level of enthusiasm after we scored the first goal," Flyers coach Ken Hitchcock said. "We were 30 to 40 percent on faceoffs and I don't think we lost a faceoff after the goal. This is usually a sign that worry is out of your game and you are just playing hockey. It's good stuff."
Gagne also assisted on Desjardins' second goal just 72 seconds later.
At 10:10 of the third, the Maple Leafs scored on the power play as former Flyer Mikael Renberg was credited with a goal off the skate of Desjardins.
Belfour made 17 of his 29 saves through the first 40 minutes, including three straight stops on former teammate Jeremy Roenick in the opening period.
Roman Cechmanek needed to stop only 18 shots but preserved the victory by going out of the crease to make a glove save on Leafs captain Mats Sundin with 2:10 remaining.
Belfour was riding a six-game winning streak and had stopped 79 straight Flyers shots since Keith Primeau beat him on a backhander in the second period of a 2-1 loss on December 20, 2001, when he was with Dallas.
But Gagne, who had just two goals in his first 24 contests before scoring twice in Tuesday's win at Florida, ended the Flyers' futility against Belfour when he lifted a one-timer from the left faceoff circle through his pads.
After defenseman Eric Weinrich created a turnover in the neutral zone, he skated up ice and drew a defender to him, leaving Gagne open.
"It was a great turnover in the neutral zone and 'Wino' (Weinrich) skated with the puck and brought the defensemen with him," Gagne said. "I was kind of open in the top of the circle and tried to go with quickness. I didn't think too much where I had to shoot. I just went as hard as I could and it went in."
Desjardins netted the game-winner when Maple Leafs defenseman Jyrki Lumme lost him on the rush, allowing him to reach to crease. After circling the net, he tapped in Gagne's rebound.
Toronto made it a one-goal game as Renberg's shot from the left side bounced off Desjardins' skate.
Earlier in the game, Tie Domi missed a golden opportunity to break the deadlock. With Cechmanek out of the crease and tied up by Jonas Hoglund as he attempted to clear the puck, Domi gained possession but hit the side of the post.
"The game was up grabs for most of it," Maple Leafs coach Pat Quinn said. "Neither team was really taking hold. You could tell early in the period that we weren't the team that was going to take over unless we changed something and we never did change it."