Lucy Griffiths was originally cast as series regular Liv Aberdine for the pilot, but was written out when the creators decided to take the show in a different creative direction for the rest of the series.

After dropping Liv Aberdine as the female lead, showrunners Daniel Cerone and David S. Goyer replaced her with the comic book character Zed, casting Angélica Celaya in the role; some of Griffiths' final pilot scenes were reshot to explain her absence from Constantine's subsequent adventures.

Because of broadcast television restrictions, John Constantine's chain-smoking habit was toned down on screen early on, though NBC later relaxed this and he was shown smoking in later episodes.

Constantine's bisexuality from the comics was not referenced on screen; showrunner Daniel Cerone explained that the trait appeared only rarely across decades of comics and said there were no immediate plans to depict it, a decision that drew criticism from the LGBTQA+ community.

Despite airing only one season, the show was renewed for continuation attempts: NBC initially declined to order more episodes past 13, and producers pitched a second season to NBC in 2015, but it was ultimately not renewed and the cast and crew were released from their contracts in mid-2015.

A script for a planned 14th episode titled "Final Girl," which would have aired had the series continued, was released online by Daniel Cerone in October 2015.

DC Entertainment released a clay stop-motion animated web series called John Con Noir, produced by Cool Town Creations, specifically to support fan efforts to get the show renewed for a second season.

Matt Ryan's Constantine was later retroactively folded into the Arrowverse continuity when he reprised the role in Arrow's fourth season episode "Haunted," directed by John Badham, who had also directed the Constantine episode "Danse Vaudou"; showrunners confirmed it was the same version of the character.

Ryan went on to voice Constantine again in a CW Seed animated web series written by J. M. DeMatteis and produced by Greg Berlanti, Sarah Schechter and David S. Goyer, and later became a series regular playing Constantine on Legends of Tomorrow before switching to a new character, Dr. Gwyn Davies, in its final season.