Chris Neil, Bobby Butler and Jason Spezza also scored for the Senators, while Colin Greening had three assists. Ottawa scored on four consecutive shots spanning the first and second period to break it open and send the reeling Penguins to their fifth straight loss.
Evgeni Malkin scored his 17th goal of the season for Pittsburgh but couldn't stop the Penguins from matching their longest losing streak in two years. Brent Johnson made just five saves on eight shots before being pulled early in the second period in favor of Marc-Andre Fleury.
Pittsburgh, a Stanley Cup favorite after Sidney Crosby's brief return in November, is eighth in the Eastern Conference at the season's midway point.
The Senators, meanwhile, are surging. Ottawa won for the sixth time in seven games without its usual flair for the dramatic. The team leads the NHL in third-period comebacks, the last coming in a 6-4 win against Philadelphia on Sunday.
The fireworks came earlier against punchless Pittsburgh.
The Penguins started Johnson in net to give Fleury the night off before a trip to Washington on Wednesday. Johnson, stellar a year ago, has struggled this season. He came in with a 3.24 goals-against average and a mediocre .885 save percentage.
Both took a hit during a nightmarish night even though the Senators were playing without defenseman Erik Karlsson, scratched moments before the opening faceoff with an upper body injury.
Ottawa hardly needed the league's top-scoring defenseman, pouncing on the Penguins after surviving an early flurry.
Pittsburgh has made a habit of playing well in games, then falling off in the final 20 minutes. The collapse came much earlier this time.
Neil got Ottawa started, taking a feed from Kyle Turris and beating Johnson easily to put the Senators up 1-0 just over midway through the first period. Butler made it 2-0 less than 3 minutes later, taking a pretty feed from Nick Foligno and tapping it into a wide-open net.
Things didn't get any better for Johnson in the second after Spezza undressed him for his 16th goal of the season. Spezza drew Johnson out of the net and then skated behind the net, all the way around the sprawled goaltender before bringing the puck back behind Johnson and banking it in off the far post.
Johnson headed to the bench to boos in favor of Fleury, though his luck was no better. Ottawa scored on its first shot against Fleury, with the puck deflecting off Michalek's skate and into the net. It appeared Michalek moved his right foot to touch the puck, but officials ruled it a good goal to make it 4-0.
Malkin gave Pittsburgh a flicker of hope by stuffing the puck past Anderson to score his 15th goal in 23 career games against the Senators.
But that was all the offense the Penguins could muster, and Pittsburgh has its first five-game regulation losing streak since the 2009-10 season.
The Penguins have scored just six goals during the slide, as injuries have mounted quickly.
Crosby remains sidelined with concussion-like symptoms as does defenseman Kris Letang. Pittsburgh center Jordan Staal is out four to six weeks with a knee injury and leading goal scorer James Neal is hobbled by a bruised right foot.
NOTES: Former Stanford quarterback and likely No. 1 NFL draft pick Andrew Luck watched the game with his father, West Virginia athletic director Oliver Luck, as a guest of Penguins owner Mario Lemieux. ... The Senators travel to New York on Thursday. ... Defenseman Paul Martin and forwards Steve MacIntyre and Colin McDonald were scratched by the Penguins. ... Pittsburgh is 16-14-3 without Crosby this season.