Newhook was selected by the Colorado Avalanche with the No. 16 pick in the 2019 NHL Draft. A native of St. John's, Newfoundland, he was the first from the province to be chosen in the first round of the NHL Draft since Daniel Cleary went No. 13 to the Chicago Blackhawks in 1997. Newhook made an immediate impact as a freshman at Boston College, where he had 42 points (19 goals, 23 assists) in 34 games. He had 16 points (seven goals, nine assists) in 12 games as a sophomore despite missing the first half of the season due to COVID-19 quarantine protocols ahead of the 2021 IIHF World Junior Championship in Edmonton, where he had six points (three goals, three assists) to help Canada to a second-place finish.

He signed a three-year, entry-level contract with the Avalanche on March 31, 2021, and after another brief quarantine, made his professional debut with the Colorado in the American Hockey League. Newhook had nine points (five goals, four assists) in eight AHL games and made his NHL debut at the San Jose Sharks on May 5. He got his first NHL point, an assist, two nights later at the Los Angeles Kings.

Newhook scored his first NHL goal in Game 3 of the 2021 Stanley Cup First Round, a 5-1 win against the St. Louis Blues. He was the third player in Avalanche/Quebec Nordiques history to score his first goal in the Stanley Cup Playoffs and first since Cale Makar in Game 3 of the 2019 Western Conference First Round against the Calgary Flames.

Newhook, a 2022 Stanley Cup champion with the Avalanche, was traded to the Montreal Canadiens on June 27, 2023, for a first- and second-round pick in the 2023 Upper Deck NHL Draft and defenseman prospect Gianni Fairbrother. He signed a four-year, $11.6 million contract July 11.

Newhoook's goal at 11:22 of overtime sent the Canadiens to the Eastern Conference Final with a 3-2 win against the Buffalo Sabres in Game 7 of the 2026 Eastern Conference Second Round. He also scored the game-winning goal in a 2-1 win against the Tampa Bay Lightning in Game 7 of the first round, making him the second player in NHL history to score multiple Game 7 series-clinching goals in a single postseason, joining Nathan Horton (2011 with the Boston Bruins).