Danny McBride said he intended the series to run longer than any of his previous shows, envisioning it as an epic, sprawling family saga comparable to The Thorn Birds, spanning cousins, great-uncles and generations.

McBride based the recurring theme of the Gemstone characters on ministers who see themselves as bigger than God, continuing a pattern from his earlier TV protagonists who all have an inflated sense of self.

For season two, Eli's backstory was inspired by the real-life Dixie Mafia and the Memphis professional wrestling scene, two subjects that had long fascinated McBride, who originally conceived the Gemstones as being modeled on Mafia families.

McBride drew a parallel between professional wrestling and televangelism, noting both industries rely on showmanship and maintaining a form of 'kayfabe'.

Principal photography for the pilot took place in Charleston, South Carolina, using the North Charleston Coliseum as the interior of Gemstone Ministries and a former Sears store at Citadel Mall repurposed as the Locust Grove Worship Center; the show kept the joke that the new church was a converted Sears.

Production on season three was temporarily shut down in September 2022 due to Hurricane Ian making landfall in South Carolina, with filming eventually wrapping in December 2022.

The song 'Misbehavin'', performed in-universe by Jennifer Nettles and Walton Goggins as siblings Aimee-Leigh and Baby Billy, became a viral hit after debuting in the episode 'Interlude'; it was written by McBride, co-star Edi Patterson, and composer Joseph Stephens to sound like a wholesome old-time country tune but with absurd lyrics like 'Runnin' through the house with a pickle in my mouth'.

John Amos appeared as Buddy Lissons in season two, which turned out to be his final television appearance before his death in 2024.