Guentzel's four goals were scored consecutively in a span of less than 14 minutes of game time, part of five unanswered goals by the Penguins to go from 4-2 down to a 7-4 advantage.
"Just trying to be around the net," Guentzel told NBC Sports after the game of his productive night. "Great plays by all of us around us. So pretty fortunate to be on the good end of them tonight."
Sidney Crosby, Carl Hagelin, Patric Hornqvist and Bryan Rust each scored one goal, with Crosby and Hornqvist adding two assists apiece. Kris Letang collected three assists himself, and Guentzel added one for a five-point night.
The team won without Evgeni Malkin, who was out with a leg injury. Goaltender Matt Murray made 21 saves on 26 shots.
The Penguins have now won nine consecutive playoff series dating back to a first-round loss in April of 2015 to the New York Rangers.
"It's a lot of fun right now," Guentzel said. "We're just trying to roll with it as it goes."
Sean Couturier scored three goals and had two assists, while Scott Laughton and Andrew MacDonald scored one goal each for the Flyers, who lost all three games at home in this series.
Couturier did it all with a torn medial collateral ligament which he revealed after Sunday's game he had suffered in a practice before Game 4, which he missed. In Game 5, he tallied the game-winning goal with 1:15 remaining.
Couturier said he will not need surgery, but would have likely missed four weeks if it happened in the regular season.
Flyers goaltender Michal Neuvirth struggled and gave up seven goals on 27 shots before an empty-netter served as the eighth tally.
Philadelphia hasn't escaped the first round of the postseason since the 2011-12 season, when the Flyers lost in Round 2 to the New Jersey Devils.
"Pretty young team and we have a lot of guys going through this for the first time around," MacDonald told reporters after the game. "It's a tough league and it's a grind and a long season."
Tied 4-4 after the second intermission, Pittsburgh struck just 30 seconds into the third as Guentzel scored only 1:24 of game time after his first goal, giving the Penguins a 5-4 advantage. Guentzel completed the natural hat trick with 7:12 left, pushing Pittsburgh ahead 6-4, before adding a fourth goal just 10 seconds later.
Couturier scored his second goal of the game just 40 seconds into the second. As the Penguins' power play just finished, Couturier broke free and gave the Flyers a 3-2 advantage.
Laughton later propelled the Flyers ahead 4-2 with a wrist shot from about 30 feet out at 12:14. It was Laughton's first career playoff goal.
The Penguins didn't wilt and got within 4-3 when Hornqvist received a pass from Guentzel and scored at 13:35.
With only 53.9 seconds left in the second, the Penguins tied the game at 4 as Guentzel redirected a shot in front past Neuvirth.
Couturier put the Flyers ahead early with an unassisted goal at 2:15 of the first. The puck remained loose in front and Couturier skated in and scored.
The Penguins responded with Crosby tying the game at 1 at 6:30. Crosby recorded points in four consecutive games in the series, with three goals and seven assists in that span.
Following a turnover by Claude Giroux, the Penguins moved ahead 2-1 when Hagelin scored at 7:17.
Philadelphia's MacDonald tied the game at 2 when he blasted a one-timer with a terrific screen in front by Wayne Simmonds.
--Field Level Media
Pittsburgh | Philadelphia | |
Jake Guentzel 5 | Points | Sean Couturier 5 |
Jake Guentzel 4 | Goals | Sean Couturier 3 |
Kris Letang 3 | Assists | Sean Couturier 2 |
N/A | Power Play Goals | N/A |
N/A | Short Handed Goals | N/A |
Matt Murray .808 | Save Percentage | Michal Neuvirth .741 |
Matt Murray 21 | Saves | Michal Neuvirth 20 |
Team | Shots | Goals | Power Play | Penalty Kill | Penalty Mins | Face Offs Won |
Pittsburgh | 28 | 8 | 0-1 | 3-3 | 10 | 24 |
Philadelphia | 26 | 5 | 0-3 | 1-1 | 6 | 28 |