During his 13-year National Hockey League (NHL) career he played with the Edmonton Oilers, Philadelphia Flyers, Phoenix Coyotes, Ottawa Senators, New York Islanders, and the Pittsburgh Penguins.

After a lacklustre training camp in the pre-season Comrie's status as local hero in Edmonton started to change dramatically,[8][9] after he elected to hold out in a contract dispute for more than 30 games into the 2003–04 season.

[13] Comrie played only 21 games for Philadelphia before being traded to the Phoenix Coyotes for Sean Burke, Branko Radivojevic, and the rights to Ben Eager.

He helped Ottawa throughout the playoffs despite having an injured shoulder that required local anesthetic to numb the pain, this prevented him from reaching down to tie his skates.

On July 5, 2007, Mike Comrie signed a one-year contract worth $3.375 million with the New York Islanders as an unrestricted free agent.

[17] Comrie would be traded back to the Senators on February 20, 2009, with Chris Campoli, in exchange for Dean McAmmond and a San Jose Sharks 2009 first round draft pick.

[20] On November 17, Comrie was placed on the NHL long term injury reserve list with mononucleosis and was expected to be out until late January.

[21] On September 3, 2010, Mike Comrie signed a one-year contract worth $500,000 with the Pittsburgh Penguins,[22] joining the franchise that drafted his uncle Fred, in 1973.

[23] On September 22, 2010, Comrie scored the very first goal inside of the new Consol Energy Center, 81 seconds into the Penguins' 5-1 exhibition game victory over the Detroit Red Wings.

[25][1] Comrie's father, Bill, and his uncles, Fred and John, are the founders of The Brick furniture company, which was sold in 2012 for $700 million.