Mittelstadt, the No. 8 pick in the 2017 NHL Draft, agreed to terms on a three-year, entry-level contract with the Buffalo Sabres on March 26, 2018, and made his NHL debut three nights later. The 19-year-old forward had his first point, an assist, on a second-period goal by Evan Rodrigues. He scored his first NHL goal in his fifth game, 2:57 into the first period of a 7-5 loss to the Tampa Bay Lightning on April 6.

Mittelstadt signed a three-year, $7.5 million contract with the Sabres on Sept. 2, 2021. He was traded to the Colorado Avalanche for Bowen Byram on March 6, 2024, and signed a three-year contract with the Avalanche on June 25. He had nine points (three goals, six assists) for Colorado in 11 Stanley Cup Playoff games, his first appearance in the postseason. The following season, he was traded to the Boston Bruins on March 7, 2025.

Mittelstadt excelled playing hockey growing up in Minnesota, and as a junior at Eden Prairie High School in 2015-16 he had nine points (four goals, five assists) in seven games to help the United States win the bronze medal at the 2016 IIHF World Under-18 Championship.

He returned to Eden Prairie for his senior season in 2016-17, had 64 points (21 goals, 43 assists) in 25 games and won the Mr. Hockey Award as the state's best senior boys player. He also showed he could handle a higher level of competition, averaging a United States Hockey League-high 1.25 points in 24 games with Green Bay.

Mittelstadt gave Sabres fans a taste of what he can do when he starred for the U.S. at the 2018 World Junior Championship in Buffalo. He tied for the tournament lead with 11 points (four goals, seven assists) in seven games and helped the U.S. win the bronze medal. Mittelstadt was named the tournament's most valuable player and its best forward.

He also had 30 points (11 goals, 19 assists), second on the team, in 34 games as a freshman at the University of Minnesota in 2017-18 before turning pro.