The 32-year-old center did not play because of an upper-body injury that will also sideline him against the Toronto Maple Leafs on Saturday. Penguins coach Mike Sullivan said Malkin is day to day but will be out until at least Tuesday against the Carolina Hurricanes.
Teddy Blueger scored his first NHL goal, and Jake Guentzel and Bryan Rust each scored twice for the Penguins (28-17-6), who have won two straight games after losing four of their previous five. Casey DeSmith made 37 saves.
WATCH: [All Senators vs. Penguins highlights]
"[Rust] is playing well," Sullivan said. "He's a guy that tends to be streaky, but when his confidence is high and he's feeling it out there, I think he's really noticeable. ... We thought [Blueger] managed really well. He's a real smart player. He sees the ice well. He has awareness away from the puck."
Bobby Ryan, Mikkel Boedker and Matt Duchene scored for the Senators (19-27-5), who lost their third in a row in their first game following their mandatory five-day break after 2019 Honda NHL All-Star Weekend. Anders Nilsson made 35 saves.
"It was like I said it would be: tougher start and get better as the game goes on," Ottawa coach Guy Boucher said. "Defensively, that's where we were rusty there. We gave them the inside too many times, and that's a team you can't give the inside to. ... So we were expecting it to be a, hopefully, tighter game by the middle of the game. When you give them three goals like that, I really liked our push. We were right there."
Blueger gave the Penguins a 1-0 lead at 3:19 of the first period when he scored with a slap shot off a pass from Matt Cullen from below the goal line. He made his NHL debut in a 4-2 win against the Tampa Bay Lightning on Wednesday after being recalled from Wilkes-Barre/Scranton of the American Hockey League on Tuesday.