Born in Omaha, Nebraska on October 6, 1994, Guentzel grew up in Woodbury, Minnesota. He played two years of varsity hockey at the Hill-Murray School (finishing 2nd in the 2012 MN State Hockey Tournament) in Maplewood, Minnesota, before committing to the University of Nebraska Omaha after his senior season.

On August 27, 2015, before Guentzel’s junior year, he was named a co-captain along with Brian Cooper after a vote by the team. After the 2015–16 season, Guentzel signed a three-year, entry-level contract with the Pittsburgh Penguins on May 23, 2016.

Guentzel began the 2016–17 season with the Penguins American Hockey League affiliate, the Wilkes-Barre/Scranton Penguins. After a recall, Guentzel made his NHL debut on November 21, 2016, against the New York Rangers, where he scored two goals on his first two shots. Despite this, the Penguins lost the game 5–2.

On March 21, 2017, Guentzel suffered a concussion on a check from Buffalo Sabres defenseman Rasmus Ristolainen. He missed the next 4 games, while Ristolainen was suspended by the league for 3 games. 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. He became the first Penguins rookie to score a playoff hat-trick, and only the second rookie in NHL history to score a hat-trick and overtime goal in the same game of the playoffs. On June 11, 2017, Guentzel won the Stanley Cup after defeating the Nashville Predators in six games. During the run, Guentzel recorded 21 points, tying Dino Ciccarelli and Ville Leino for points by a rookie in a single post-season. His 13 goals was one off of Ciccarelli’s record.

The 2018–19 season marked the last year Guentzel was on his entry level rookie contract. The Penguins began the season with a slow start, landing near the bottom of the league in early November. On November 24, 2018, Guentzel recorded his first regular season hat trick in a 4–2 win over the Columbus Blue Jackets. The following month, on December 27, the Penguins re-signed Guentzel to a five-year, $30 million contact. Guentzel recorded his second regular season hat trick in a 7–4 win over the Anaheim Ducks on January 11, 2019. His hat trick was the first by a Penguins player ever against the Anaheim Ducks. After a two-goal game the following night against the Los Angeles Kings, Guentzel was named the NHL’s Third Star of the Week.

In the 2019–20 season, Guentzel put up 20 goals and 23 assists in 39 games for the Penguins, and was voted in to play in the 2020 NHL All-Star Game. On December 30, 2019, Guentzel recorded his 200th career point as he scored a goal against the Ottawa Senators. 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 . The next day, Guentzel underwent successful shoulder surgery that sidelined him for 6 months. 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.