DeMelo tied it at 1-1 at 8:49 of the second with a one-timer from the right point after Ottawa won a face-off in the Montreal zone.
The Canadiens responded with four straight goals, including three in 3:39.
"We were right there," Senators coach Guy Boucher said. "It's 1-1, five minutes left in the second period, and we gave it away. We gave them a goal, and right away we tried to get it back and we overdo it, and again it bites us in the butt."
Domi scored on a one-timer from the slot on a pass from Drouin for a 2-1 lead at 14:38.
Domi scored his 13th at 17:29 for a 3-1 lead. Drouin drove the right side and dropped a backhand pass to Domi, who scored on a wrist shot from the right circle.
"He's just so good," Domi said. "He's easy to play with, honestly. When you start knowing what a guy is going to do with the puck it's pretty cool, and he's just unbelievable. The talent he has with the puck is with some of the elite players in the NHL, so it's fun to play with him and we're lucky to have him."