The Penguins (27-12-8) won despite playing without Crosby and Malkin, who each missed the game with a lower-body injury.
Brandon Sutter gave Pittsburgh a 4-3 lead 7:52 into the third period, and forward Patric Hornqvist scored an empty-net goal with 27.3 seconds remaining. Hornqvist returned after missing the past 11 games because of a lower-body injury and tied Chris Kunitz for third on Pittsburgh with 14 goals.
"It's nice to get the first one out of the way," Hornqvist said. "Obviously, missing a month, you lose a lot of details in your game and it's nice to get the first out of the way and get the big win and hopefully we get better here every game."
Letang returned after missing one game because of a concussion and said returning in the way he did was "pretty cool."
"The main thing is the win," Letang said. "I think the last time we played against them, they banged us pretty hard. They were finishing all of their checks, and again that's what they tried to do. They tried to be physical on us and get us off our game, but everybody stuck to it."
The Jets (26-15-8) had a five-game winning streak end. Winnipeg/Atlanta has lost 14 consecutive games at Pittsburgh.
The Penguins trailed 3-2 early in the third period, but forward David Perron scored his sixth goal in nine games with Pittsburgh to tie it. With Blake Wheeler in the penalty box for slashing, Perron dug a rebound off a Letang slap shot past Pavelec at 4:23.
Penguins coach Mike Johnston said he was impressed with Letang's performance, especially against a physical team.
"When he's skating like that, he can jump up into the play and then he can get back," Johnston said. "That's what he did tonight. He had a great balance to his game, and when he was going back for a couple of pucks there in the third period, they're a heavy forechecking team, it's tough when you're going back for pucks like that, and I just thought every decision he made, he made with speed and he made it quick."
After surrendering a one-goal lead late in the second period, Winnipeg reestablished that lead within the first minute of the third. Jets forward Chris Thorburn received a stretch pass from Evander Kane and had the puck poked off his stick by Penguins defenseman Christian Ehrhoff to Lowry, who got a wrist shot by Thomas Greiss to give the Jets a 3-2 lead 59 seconds into the third.
Lowry and Thorburn each had one goal and one assist.
Thorburn's goal came early in the second period to tie the game 1-1, following a lackluster first period for Winnipeg. Shortly after being released from the penalty box, Thorburn beat Kunitz to a pass from Lowry and tipped the puck over Greiss' blocker 2:13 into the second.
Thorburn has scored one goal in three of his past four games after scoring one goal through his first 44 games. He credited playing with Lowry and Kane for the recent boost in his play.
"Every time you play with some new guys, there's a little bit of excitement, different excitement," Thorburn said. "So we made some good plays out there, simple plays using our size, and we got rewarded for it. So hopefully it continues moving forward, but it doesn't feel as good as it does without the win."
The Jets had a chance to take a 2-1 lead about two minutes later when Jim Slater rung a slap shot off of the left post, but would eventually take a one-goal lead when Jacob Trouba's slap shot avoided the post and made its way through a screen by Mathieu Perreault to get by Greiss with 7:13 remaining in the first.
Winnipeg seemed poised to carry the lead into the third, but Steve Downie's goal with 4.6 seconds remaining in the second tied the game 2-2. Downie slid a pass to defenseman to the right faceoff circle, where Letang one-timed a slap shot off of Pavelec's pads. The rebound bounced to Downie, who pushed a wrist shot into the net for his ninth goal.
"I don't think our gap control was really good," Jets coach Paul Maurice said. "We didn't have a whole lot of pressure on the puck. We ended up leaving a lot of shots in the middle, off shots from the wing."
The Penguins dominated the first period, in large part because of Perron's performance.
A few minutes after stick-handling through two defensemen and sending a wrist shot wide of the Winnipeg net, Perron played a key role in setting up Pittsburgh's first goal. He carried the puck past the goal line to the right of the net, drawing Pavelec toward the right post, and sent a pass out in front, where forwards Nick Spaling and Beau Bennett were converging.
Spaling beat Perreault to the pass and tipped it into the open net to give Pittsburgh a 1-0 lead 7:09 into the first.
"I think it was a little sloppy, especially in the first period," Lowry said. "There were some turnovers that weren't very characteristic of our hockey club. We weren't finishing all of our checks and we were allowing them to break out of the zone pretty cleanly. I think once the second period got going, we started to get our legs under and we started to play better.
"But obviously, it wasn't the way we wanted to play."