A TV adaptation of the comic was first planned in 2006 when Mark Steven Johnson bought the rights and pitched it to HBO, wanting it to be an exact 6-year adaptation of all 75 issues rather than a two-hour film.

HBO's production was cancelled around 2008 after a new network head deemed the show too violent and demanded a revamp that Johnson refused to make.

After HBO dropped the project, Neal H. Moritz acquired the film rights for Columbia Pictures in 2008, with John August writing a script and Sam Mendes attached to direct before he left to make Skyfall; D.J. Caruso then took over but the film stalled.

AMC's series was officially developed starting in November 2013, with Seth Rogen and Evan Goldberg writing the pilot alongside showrunner Sam Catlin, and comic creators Garth Ennis and Steve Dillon serving as co-executive producers.

The original unaired pilot version featured Elizabeth Perkins as a female character named Vyla Quincannon, but the writers ultimately changed the role to a male character, Odin Quincannon, to match the comics, played by Jackie Earle Haley.

The character Herr Starr was briefly introduced in the first season episode 'The Possibilities' played by a different actor before Pip Torrens took over the role as a main cast member from season two onward.

Seth Rogen confirmed in May 2015 that he and Evan Goldberg would direct the pilot episode themselves, which had just begun filming.

After each new season's premiere episodes, AMC aired a live aftershow called Talking Preacher, hosted by Chris Hardwick using the same format as his other aftershows Talking Dead, Talking Bad, and Talking Saul.