Jack Campbell was pulled after allowing five goals on 21 shots through the first two periods for the Maple Leafs (2-3-1). Michael Hutchinson made 10 saves in relief after starting a 5-3 loss to the San Jose Sharks on Friday.
"I have a lot of thoughts, obviously. Not many good ones," Toronto coach Sheldon Keefe said. "It's tough playing from behind. (We've) been doing it too much lately. But Pittsburgh, full marks. They were fast and competitive all through the game. They don't make it easy on you.
"Sometimes when we were careless with the puck, they made us pay for it. That was pretty consistent all the way through."
The Penguins had a 1-0 lead for 51 seconds after a shot from Pettersson went off O'Connor at 11:53 of the first period.
"I think a lot of it is just battling," O'Connor said. "Something I didn't do as well, maybe, last game. So, I tried to focus on it a bit."
Jason Spezza tied it 1-1 at 12:44 with his third goal in six games. Pierre Engvall sent a shot to the right of the net, where Spezza scored on a wrist shot.
Mike Matheson and Jason Zucker scored 15 seconds apart to give the Penguins a 3-1 lead early in the second period.
Matheson drove past Maple Leafs defenseman Jake Muzzin and scored on a wraparound to make it 2-1 at 1:38. Zucker made it 3-1 with a snap shot at 1:53.
O'Connor shot off Muzzin and in for his third NHL goal, extending the lead to 4-1 at 11:01 of the second.
"The mood ain't great," Muzzin said. "You lose like that, it's not a good mood. But it's early in the season. It's a test for us. Let's see how we respond."
Pettersson took a pass from Evan Rodrigues before taking a wrist shot from the slot to make it 5-1 at 13:59 of the second. Pettersson scored nine points (two goals, seven assists) in 47 games last season.
"I think Marcus is playing with a whole lot of confidence," Penguins coach Mike Sullivan said. "And I think because of that, his whole overall game has just improved. His gaps are better, he's making better decisions with the puck, he's more assertive in all aspects of his game."