At 17, Hanifin became the youngest player to suit up for Boston College, and a year later he became the only defenceman from the 2015 NHL Draft to start the season in the League that fall when he made his debut with the Carolina Hurricanes against the Nashville Predators on Oct. 8, 2015.

Hanifin, chosen in the first round (No. 5) by Carolina, scored his first NHL goal against the Anaheim Ducks on Nov. 16, 2015, and became a regular on the Hurricanes blue line.

He was coming off his best offensive season in the NHL (32 points; 10 goals, 22 assists) in 2017-18 when he was traded to the Calgary Flames on June 23, 2018, with center Elias Lindholm for defenseman Dougie Hamilton, forward Micheal Ferland and defenseman prospect Adam Fox. After six seasons in Calgary, Hanifin was traded to the Vegas Golden Knights in a three-way deal that included the Philadelphia Flyers on March 6, 2024. He signed an eight-year, $58.8 million contract (average annual value of $7.35 million) with the Golden Knights on April 11, preventing him from becoming an unrestricted free agent.

Hanifin played for the runner-up United States at the 4 Nations Face-Off and won gold with Team USA at the Olympic Winter Games Milano Cortina 2026, the country's first in men's Olympic hockey since the 1980 Lake Placid Games. He was captain of the United States team that won gold at the 2014 U-17 World Hockey Challenge and again at the 2014 IIHF World Under-18 Championship.

A product of the Saint Sebastian's School in Needham, Massachusetts, Hanifin passed on an opportunity to play junior hockey for Quebec of the Quebec Major Junior Hockey League and instead honored a commitment he made in 2011 to play for Boston College.

During his only season with the Eagles, Hanifin played in 37 of 38 games and had five goals, 18 assists and a plus-12 rating that helped BC finish tied for second with eventual national champion Providence in Hockey East.

Hanifin represented the United States at the 4 Nations Face-Off and was named to Team USA's roster for the Olympic Winter Games Milano Cortina 2026. He was captain of the United States team that won gold at the 2014 U-17 World Hockey Challenge and again at the 2014 IIHF World Under-18 Championship.