Gustafsson waited three years after he was drafted to make his NHL debut.

Gustafsson developed with the Djurgarden hockey program in his native Sweden, and made his debut in the Swedish Hockey League as a 19-year-old during the 2011-12 season. The Edmonton Oilers liked what they saw and selected the defenseman in the fourth round (No. 93) of the 2012 NHL Draft.

Gustafsson spent 2012-13 with Djurgarden and then played two seasons with Frolunda in the SHL. He tied for fifth among SHL defensemen in 2014-15 with 29 points (five goals, 24 assists) in 55 games, then signed a two-year contract with the Chicago Blackhawks on April 30, 2015.

He made his NHL debut against the Minnesota Wild on Oct. 30, 2015, and had an assist for his first NHL point. Gustafsson split 2015-16 between the Blackhawks and Rockford, their American Hockey League affiliate, and played for Sweden at the 2016 IIHF World Championship.

Gustafsson played the 2016-17 season in the AHL, and signed a one-year contract to remain in Chicago on July 14, 2017.

He started 2017-18 with Rockford but was called up to the Blackhawks on Jan. 9, 2018. He scored his first NHL goal in his first game, and added an assist against the New York Islanders on Jan. 20, 2018.

Gustafsson signed a two-year contract with the Blackhawks on March 6, 2018. He played for the Calgary Flames, Philadelphia Flyers, Montreal Canadiens and Washington Capitals, and was traded to the Toronto Maple Leafs by Washington for defenseman Rasmus Sandin on Feb. 28, 2023.

Gustafsson signed a one-year contract with the New York Rangers on July 1, 2023. He signed a two-year, $4 million contract with the Detroit Red Wings on July 1, 2024.