Crosby earned another assist during a power play when Letang fired a slap shot that Hornqvist deflected past Jhonas Enroth at 3:30.
The home crowd gave a sarcastic cheer when Tyler Myers came out of the penalty box and recorded Buffalo's first shot on goalie Marc-Andre Fleury at 13:24.
"The only thing we have control over is put them on the ice," Sabres coach Ted Nolan said. "We can't skate for them, we can't shoot for them, we can't compete for them. It's one of those things. They have to compete, they have to work."
The Penguins were ready to work, too.
Letang scored his second goal with a point shot at 15:04, with help from Crosby, who picked up his third assist of the period.
Pittsburgh stretched its lead to 4-0 while Buffalo's Drew Stafford served a slashing penalty. Hornqvist moved into the right circle and took a pass from Kunitz to beat Enroth over the right shoulder at 4:56 of the second period.
"Your effort level and your compete level has to be there, so I think we give ourselves a chance to create things when we're working hard and competing," Crosby said.
Fleury wasn't called upon much -- Buffalo managed only just 20 shots for the game -- but he responded by making a glove save when Matt Moulson was left alone in the slot.
Bortuzzo made it 5-0 when he was allowed to skate around the slot and lift the puck over a prone Enroth at 14:01.
Girgensons ended Fleury's shutout bid with 3:08 left in the second with a deflection of Josh Gorges' shot.
Malkin restored Pittsburgh's five-goal lead when he scored at 19:45 of the second.
"To get scored on that many times, it's embarrassing," Gorges said. "I'm embarrassed for myself. I've got to do way better than that. That's all there is to it."
NOTES: It was Crosby's first five-assist game since March 10, 2013. ... Enroth made 33 saves in the loss.