Barr's debut as a comics professional came in DC Comics' Detective Comics #444, for which he wrote an 8-page back-up mystery feature starring the Elongated Man in late 1974/early 1975. His credits then skip ahead four years, when he wrote a further couple of back-up features for Detective Comics and House of Mystery as well as an issue of Captain America (#241) for Marvel in January 1980. By mid-1980 he was writing regularly for both DC and Marvel, and in 1981 penned stories for Marvel Team-Up and Mystery in Space as well as various Batman and Green Lantern titles, among others.

Legion of Super-Heroes #277 (July 1981) saw him take on editorial duties at DC, while writing issues of DC's Star Trek comic, for whom he created the native American character Ensign Bearclaw and a pacifist Klingon named Konom. In December 1982, he debuted the first issue of one of the earliest maxi-series, Camelot 3000, with art by Brian Bolland, one of few titles Bolland provided full artwork on.

In August 1983, he created what may well be his most enduring work, the monthly title Batman and the Outsiders (with art by Jim Aparo), which he also wrote for every issue of the first series, and its Baxter paper spinoff, The Outsiders.

His other comics work includes Mantra and Maze Agency as well as the 1987 OGN hardcover book Son of the Demon (with art by Jerry Bingham), proceeds from which reputedly "restored DC Comics to first place in sales after fifteen years." This title, and Barr's work on Batman with artist Alan Davis have been cited by Grant Morrison as key inspirations for his recent (2006) run on the Batman title.

Most recently he wrote a two-part story for the pages of DC's Classified (#47-48, Jan-Feb 2008), returned to the Outsiders with Outsiders: Five of a Kind...Katana/Shazam #1 (Oct 2007), contributed to Tokyopop's Star Trek: The Manga, and relaunched Maze Agency at IDW Publishing.

He has also scripted many of Bongo Comics' Simpsons titles, including a Christmas story for 2010.

In May 2010, the Invisible College Press published Barr's science fiction/fantasy novel, Majician/51, about the discoveries of a scientist working at Area 51. Its website can be found at http://www.invispress.com/M51/

FantasticFiction notes that:

"Mike W. Barr has written [for] every one of the first four incarnations of Star Trek: Star Trek, The Next Generation, Deep Space Nine and Voyager -- in either comic book or other formats."It is also pointed out that Barr's Batman stories and scripts have been adapted into several mediums, including for episodes of The Animated Series.