Guentzel gave the Pittsburgh Penguins a lift during the 2016-17 regular season and was indispensable during their run to the Stanley Cup.

Selected by the Penguins in the third round (No. 77) of the 2013 NHL Draft, Guentzel signed a three-year, entry-level contract May 23, 2016 after three seasons at the University of Nebraska-Omaha. He made his NHL debut Nov. 21, 2016 and scored two goals against the New York Rangers, including one on his first shot and first shift. He was a regular by mid-January and finished with 33 points (16 goals, 17 assists) in 40 games.

But that was just a warmup for his performance during the Stanley Cup Playoffs.

Guentzel led all scorers in the postseason with 13 goals and tied the playoff record for points by a rookie with 21, matching Dino Ciccarelli of the Minnesota North Stars in 1981 and Ville Leino of the Philadelphia Flyers in 2010. He also scored five game-winning goals.

Guentzel became the second rookie in NHL history to have a hat trick and score an overtime goal in the same playoff game when he helped the Penguins rally for a 5-4 victory against the Columbus Blue Jackets in Game 3 of the Eastern Conference First Round (Gerry Plamondon, Montreal Canadiens, 1949). He also became the first Penguins rookie to score three goals in a playoff game.

Guentzel scored the winning goal in Game 1 and Game 2 of the Stanley Cup Final against the Nashville Predators to help the Penguins become the first repeat champion in 19 years.

He increased his point total to 48 (22 goals, 26 assists) in 2017-18 and had 21 points (10 goals, 11 assists) in 12 playoff games.

Guentzel scored 40 goals and had 76 points in 2018-19, playing 82 games for the second consecutive season. He signed a five-year contract with the Penguins on Dec. 27, 2018.

Guentzel, a two-time 40-goal scorer in eight seasons with the Penguins, was traded to the Carolina Hurricanes with Ty Smith on March 7, 2024, for Michael Bunting, forward prospects Vasily Ponomarev and Ville Koivunen, forward Cruz Lucius, a conditional first-round pick in the 2024 NHL Draft, and a conditional fifth-round pick in the 2024 draft.

On June 30, 2024, the Hurricanes traded Guentzel to the Tampa Bay Lightning for a third-round pick in the 2025 NHL Draft. The next day he signed a seven-year, $63 million contract, an average annual value of $9 million.

Guentzel played for the runner-up United States at the 4 Nations Face-Off and won gold with Team USA at the Olympic Winter Games Milano Cortina 2026, the country's first in men's Olympic hockey since the 1980 Lake Placid Games. He scored his 300th NHL goal in Tampa Bay's 6-3 win at the Minnesota Wild on March 24, 2026.