Rescue Me was created by Denis Leary and Peter Tolan, who also served as executive producers and head writers, and the series was produced by Cloudland Company, Apostle, DreamWorks Television, and Sony Pictures Television.

Season 5 was delayed until March 2009 because of the 2007–08 Writers Guild of America strike, but Denis Leary revealed on The Daily Show with Jon Stewart that all 22 episodes would air on consecutive weeks.

At a December 2008 appearance at Book Soup in West Hollywood, Leary revealed that season 5 would include a retrospective look into the events leading up to and surrounding 9/11 from each character's perspective.

Michael J. Fox joined the cast in season 5 as Janet's new love interest, and he won a Primetime Emmy Award for Outstanding Guest Actor in a Drama Series for the role.

Framed fire-themed illustrations by retired Las Vegas firefighter Allan Albaitis appeared throughout all seven seasons, generally visible on background walls of main characters and displayed in fire department offices.

The main title theme is a shortened version of 'C'mon C'mon' by The Von Bondies, and that song along with several others featured on the show were picked by Denis Leary's son.

The show's underscore and end title theme were composed by Christopher Tyng, who had also scored Leary's previous television series The Job.

Michael Lombardi's real-life band, Apache Stone, performed several times on the show, although their music does not appear on the official soundtrack released in 2006.

The series premiere drew almost 4.1 million viewers, ranking eighth all-time for series premieres on basic cable, and earned Denis Leary and Peter Tolan an Emmy nomination for Outstanding Writing in a Drama Series.

Rescue Me received critical acclaim on Metacritic across its run, scoring 86, 89, 90, 85, 84, 77, and 73 out of 100 for seasons 1 through 7 respectively.