Kerfoot saw the Colorado Avalanche as his quickest route to the NHL.

The New Jersey Devils selected Kerfoot in the fifth round (No. 150) of the 2012 NHL Draft after one season with Coquitlam of the British Columbia Hockey League in which he won the BCHL Coastal Conference rookie of the year award. He returned to Coquitlam for the 2012-13 season, but an injury limited him to 16 games.

Kerfoot moved his development to Harvard University in 2013-14. As a sophomore in 2014-15 he was third on the team with 30 points (eight goals, 22 assists) in 27 games and helped Harvard win the ECAC championship.

He improved his point total to 34 (four goals, 30 assists) in 2015-16, and as captain in 2016-17 he led the way with 45 points (16 goals, 29 points). He helped Harvard repeat as ECAC champion and was named a finalist for the Hobey Baker Award, given to the top player in NCAA Division I.

Kerfoot passed on signing with the Devils and became an unrestricted free agent; on Aug. 24, 2017, he signed a two-year contract with the Avalanche. Kerfoot made his NHL debut against the New York Rangers on Oct. 5, 2017, and got his first point, an assist on Tyson Barrie's game-winning goal in the third period.

He scored his first NHL goal in his fourth game, against the Boston Bruins on Oct. 11, and played a consistent top-nine role for the Avalanche all season to help them reach the Stanley Cup Playoffs after they finished with the fewest points in the NHL in 2016-17.

After finishing with 43 and 42 points in his first two NHL seasons, Kerfoot was traded to the Toronto Maple Leafs on July 1, 2019, and signed a four-year contract three days later. He settled in as the third-line center behind Auston Matthews and John Tavares, finishing with 28 points (nine goals, 19 assists) in 65 games despite missing time early in the season with a broken jaw.

Kerfoot signed a two-year contract with the Arizona Coyotes on July 1, 2023.