Comrie was drafted in the third round out of the University of Michigan. He was selected ninety-first overall, in the 1999 NHL Entry Draft, by his hometown Edmonton Oilers.
Reception in Edmonton
When Comrie's NHL career began with the Oilers during the 2000-2001 season, he was one of most beloved Oilers on the team, playing the role of the "local hero". However, after his lengthy holdout in the 2002-03 season and subsequent departure from the team, Comrie became one of the most hated Oilers in team history. Whenever he returns to Edmonton, Oilers fans soundly boo him whenever he touches the puck. Many fans, and even some offhand references in The Edmonton Sun tout Comrie as one of the most hated men in Oilers history, along with Peter Pocklington,Ty Conklin and Chris Pronger. This is partly due to his alleged affair with teammate Tommy Salo's wife which led to friction between himself and the rest of the team and caused Comrie to make derogatory comments about the team and the city of Edmonton. During the 2002-03 season, amidst personal differences with Oilers general manager Kevin Lowe, Comrie was traded to the Philadelphia Flyers in exchange for Jeff Woywitka, a first round selection in 2004 (Rob Schremp), and a third round selection in 2005 (Dan Syvret).
Comrie played only 21 games for Philadelphia before being traded to the Phoenix Coyotes for Sean Burke, Branko Radivojevič, and the rights to Ben Eager.
Post-departure from Philadelphia
In August 2006, Phoenix re-signed Comrie to a one-year contract worth $3 million (US). On January 3rd, 2007, Comrie was traded to the Ottawa Senators in exchange for Senators prospect Alexei Kaigorodov. Comrie scored his first goal for the Senators versus the Boston Bruins on January 9th at Scotiabank Place in Ottawa, Ontario. When Comrie scores a goal at Scotiabank Place, his goal song is "Black Gloves" by Goose.
On 5 July 2007 Mike Comrie signed a 1-year contract with the New York Islanders.