The shutout was DeSmith's second of the season and eighth in 69 NHL starts.
Jeff Carter and Bryan Rust scored for the Penguins (29-11-8), who have won two straight since the All-Star break after losing their previous four.
"It's a full team game, and we played great tonight," DeSmith said. "I just happened to be behind everybody. … I was fortunate to make some saves tonight. Everybody in front of me did the rest."
Matt Murray made a season-high 42 saves in his first game against his former team for the Senators (16-23-4), who had won their previous two games. The goalie played five seasons for Pittsburgh, winning the Stanley Cup in 2016 and 2017, before being traded to Ottawa on Oct. 7, 2020.
"I tried to take it as just another game," Murray said. "It's been two years in the making, though. I've missed them a couple times with the weird alignment last year. So nice to get it over with, I'll say that.
"It was weird, for sure, at the start of the game. I know, firsthand, how dangerous those guys are offensively. They came to play tonight. I've seen them in practice for so many years. It was different, for sure. It was a weird feeling."
Carter gave Pittsburgh a 1-0 lead at 7:25 of the second period on a one-timer from the slot set up by Kris Letang. The goal ended Carter's drought of five games without a point since having an assist against the Arizona Coyotes on Jan. 25.
"This is a pretty solid 60 minutes, throughout the lineup," Carter said. "We played fast. They're a good team. They played fast. They're a skilled team. They got some chances. [DeSmith] made some big saves for us. But I thought it's probably our most complete game in a long time. It's a good step for us."