A fourth-round pick (No. 121) by the Detroit Red Wings at the 2008 NHL Draft, Nyquist played three seasons at the University of Maine and was a finalist in 2010 for the Hobey Baker Award, given to the player voted the best in NCAA men's ice hockey, when he led the nation in scoring with 61 points (19 goals, 42 assists).

After leaving college in 2011, Nyquist played the majority of the next three seasons in the American Hockey League and helped Grand Rapids win the Calder Cup in 2013, when he scored seven points (two goals, five assists) in 10 playoff games.

Nyquist began the 2013-14 season at Grand Rapids before being called up by the Red Wings; he scored two goals in his first game of the season against the Carolina Hurricanes on Nov. 21, 2013. During a 10-game stretch from March 16-April 2, 2014, Nyquist scored 12 goals and had 14 points. He finished with 28 goals and 48 points in 57 games.

In Nyquist's first full NHL season in 2014-15, he scored 54 points (27 goals, 27 assists) in 82 games. On July 10, 2015, Nyquist signed a four-year contract with Detroit.

Nyquist became an unrestricted free agent after the season and signed a four-year contract with the Blue Jackets on July 1, 2019. He was traded to the Minnesota Wild on Feb. 28, 2023, for a fifth-round pick in the 2023 NHL Draft, and signed a two-year, $6.37 million contract with the Nashville Predators on July 1, 2023. He was traded to the Wild by the Predators on March 1, 2025, for a second-round pick in the 2026 NHL Draft.