Almost all of Isbell's family, except his parents, were musicians, and his father was an avid music listener. After some work as a songwriter, in 2001 Isbell joined the rock band Drive-By Truckers while they toured in support of their album Southern Rock Opera. Isbell recorded and wrote with the Truckers for their next three albums.

Jason Isbell and The 400 Unit's eponymous album was released on February 17, 2009, on Lightning Rod Records. Jason Isbell and The 400 Unit is Isbell's second solo release and his first release with his band The 400 Unit.