Aleksander Barkov had four shots on goal in 21:27 in the center's return after missing three games with a lower-body injury for Florida (29-19-6), which is 1-3-1 following a season-high six-game winning streak. Sergei Bobrovsky made 19 saves.
The Panthers have lost two straight games in regulation for the first time since losing three in a row Dec. 10-14. They are two points behind the Toronto Maple Leafs for third in the Atlantic Division.
"We just couldn't find a way to get the win," Barkov said. "Obviously, that's a team and an organization, Pittsburgh, they've been winning a lot lately. You've got to learn from those teams how to find a way to win games, even if you're not playing at your best."
Letang put the Penguins ahead 1-0 at 6:30 of the first period when he scored unassisted on a breakaway after exiting the penalty box. The puck got past Panthers defenseman Aaron Ekblad at the blue line, and Letang skated it from center ice and beat Bobrovsky with a backhand.
Teddy Blueger made it 2-0 at 10:44. Florida defenseman MacKenzie Weegar mishandled the puck after Pittsburgh defenseman Jack Johnson played it toward the net, and Blueger chipped it past Bobrovsky near the right post.
Mike Hoffman, who had a goal and an assist, cut it to 2-1 on a wrist shot from the right face-off circle at 17:22. It was his third goal in four games.
"We played well, but a couple of their goals are maybe a little bit too easy for them to get," Hoffman said. "There are good teams in this league, and they're going to earn goals themselves, but we can't be giving up too many free ones."
Crosby extended the lead to 3-1 by redirecting a pass from Jared McCann on the power play at 3:50 of the second period.
"They move the puck well. They have a lot of speed," said Crosby, who has 13 points (five goals, eight assists) in nine games since returning from core muscle surgery. "The best way to play against that is to have the puck in their end. So I thought we did a pretty good job of that."
Brett Connolly took a pass from Vincent Trocheck and scored with a slap shot from the left circle to cut it to 3-2 at 4:59 of the second.