The show features a prominent gay character, Jesus de Sade, whose sexuality is an acknowledged part of his identity. While the show's irreverent tone applies to all characters, his queer identity is neither a central theme for upliftment nor a specific target for degradation, resulting in a neutral overall portrayal.

Preacher includes Jesus de Sade, a transsexual character managing a brothel in Hell. Their identity is present but incidental to their role, neither serving as a source of mockery nor explicit affirmation. The portrayal is neutral, avoiding strong positive or negative arcs regarding trans identity within the show's fantastical and often irreverent setting.

The show features Tulip O'Hare, a skilled and violent character, who repeatedly engages in and wins close-quarters physical fights against multiple male opponents using brawling and tactical skills.

Tulip O'Hare, a character depicted as white in the original Preacher comic series, is portrayed by Ruth Negga, an actress of Black and Irish descent, in the television adaptation. This constitutes a race swap.

The show consistently portrays Christian institutions, figures, and interpretations (especially fundamentalist ones) as deeply flawed, hypocritical, violent, and often absurd. It satirizes blind faith and the abuse of power in the name of religion, with God himself often depicted as absent or uncaring.