[4] In his sophomore season, he helped guide the Mavericks to their first showing in the Frozen Four, scoring the team's only goal in a 4–1 loss to the Providence Friars.

[8] After a recall, Guentzel made his NHL debut on November 21, 2016, against the New York Rangers; he scored two goals on his first two shots.

[11] On April 16, 2017, he scored a hat-trick, which included the game-winning goal in overtime, to put the Penguins up 3–0 in their first-round playoff series against the Columbus Blue Jackets.

[13] Guentzel began the 2017–18 season in the NHL, putting up a career high 48 points in 82 games to help the Penguins qualify for the 2018 Stanley Cup playoffs.

[16] On November 24, 2018, Guentzel recorded his first regular season hat trick in a 4–2 win over the Columbus Blue Jackets.

[20] After a two-goal game the following night against the Los Angeles Kings, Guentzel was named the NHL's Third Star of the Week.

However, immediately after scoring the goal, Guentzel tripped over the stick of Senators defenseman Thomas Chabot, and crashed shoulder first into the boards behind the net.

[23] Guentzel was expected to miss the remainder of the season, but with the NHL pushing the start of the Stanley Cup Playoffs into early August due to the COVID-19 pandemic, he was able to recover and join his teammates for the postseason.

[24] Despite a healthy Guentzel available to the team, the heavily favored Penguins were upset by the Montreal Canadiens in the Qualifying Round of the tournament in four games.

Although he would return to the game and score two goals and an assist in the 6–1 victory, the streak would end as head coach Mike Sullivan ruled him out for a few weeks on December 8.

[33] On March 7, 2024, while on the injured reserve list, Guentzel was traded to the Carolina Hurricanes, along with Ty Smith, in exchange for Michael Bunting, Ville Koivunen, prospect Cruz Lucius, Vasili Ponomaryov, and two conditional 2024 draft picks.

[36] With his contract expiring in the 2024 offseason, Guentzel was traded to the Tampa Bay Lightning on June 30, 2024, in exchange for a third-round pick in 2025.

[39] Guentzel was a stick boy for the team when future Penguins teammate Phil Kessel played for Minnesota.