The Bruins selected Brandon Carlo in the second round, 37th overall, of the 2015 NHL Entry Draft. Carlo won a silver medal at age 16 playing with the United States at the 2013 Ivan Hlinka Memorial Cup and twice competed in the IIHF World Junior Championship, winning bronze in 2016. He was selected by the Boston Bruins in the second round (No. 37) of the 2015 NHL Draft and signed an entry-level contract on Sept. 25 of that year.

After one more season with Tri-City of the Western Hockey League, Carlo made his professional debut with Providence of the American Hockey League on April 1, 2016, playing seven games to end the season.

The following season, Carlo made the Bruins out of training camp. He had an assist in his first NHL game at the Columbus Blue Jackets on Oct. 13, 2016, and scored his first NHL goal at the Winnipeg Jets four days later.

Often playing with veteran defenseman Zdeno Chara, Carlo had 16 points (six goals, 10 assists), was plus-9 and averaged 20:49 (wrong number) of ice time in 82 games. However, a concussion sustained in the final game of the regular season kept Carlo out of Boston's six-game loss to the Ottawa Senators in the Eastern Conference First Round of the Stanley Cup Playoffs.

Carlo would become a mainstay on the Bruins back end, playing 76 games (six points) in 2017-18 and 72 games (10 points) in 2018-19, when he helped the Bruins advance to the Stanley Cup Final before losing to the St. Louis Blues in seven games.

Before the 2019-20 season was paused on March 12 due to concerns surrounding the coronavirus, Carlo had an NHL career high in assists (15) and points (19) in 67 games.