The show was independently produced and released by the McElroy brothers from April 2010 until it joined the Maximum Fun network of podcasts in January 2011. In 2010, the show was consistently listed among the top 10 comedy podcasts on iTunes. Writing for The A.V. Club, critics David Anthony and Colin Griffith both counted MBMBaM as one of their top 10 podcasts of 2012. A TV series based on the podcast premiered on Seeso in February 2017.

"(It's a) Departure" by John Roderick & The Long Winters (from the album Putting the Days to Bed) has served as the primary theme song for My Brother, My Brother and Me since the show joined the Maximum Fun network on January 17, 2011. Prior to this, the show's theme song was "Take a Chance on Me" by ABBA, while "Root to This" by Fear of Pop and later "Play Your Part (Pt. 2)" by Girl Talk was used as a closing theme.

Episodes of the show are occasionally performed and recorded in front of live audiences at venues in cities such as Los Angeles, New York City and Huntington; the format remains the same, including recurring segments such as Munch Squad, with the addition of a section where the brothers take questions from the audience. A special episode called "The Adventure Zone" was released on August 18, 2014, shortly after Justin and his wife Sydnee had a baby. It featured the brothers playing a game of Dungeons & Dragons with their father, Clint. The Adventure Zone was later spun off into its own podcast on the Maximum Fun network.

Justin, the oldest brother, lives in Huntington, West Virginia, and works as an editor-at-large at Polygon, a video game website. He also co-hosts the medical history podcast Sawbones with his wife, Dr. Sydnee McElroy. In 2016 Justin co-invented "asynchronous podcasting" with Roman Mars, creating the first episode of Smart Stuff which began in episode 316 of MBMBaM and was completed in episode 225 of 99% Invisible, hosted by Mars. Justin also hosted a YouTube show called "Things I Bought at Sheetz" with Dwight Slappe. He and Griffin McElroy host a Gaming comedy show for Polygon called Monster Factory in which they attempt to create hideous characters in video game character creators.

The McElroy Brothers appeared on the July 24, 2017 episode of @midnight, during which host Chris Hardwick publicly acknowledged that @midnight was ending.