Louie features LGBTQ+ characters, notably a transgender woman and a lesbian comedian. The show portrays these characters with dignity, though it also explores the protagonist's awkward and sometimes uncomfortable reactions to their identities. The net impact is neutral, as the depictions neither strongly affirm nor denigrate LGBTQ+ identities, instead presenting them as part of a complex reality.

The show features a trans woman character, Vanessa, who is depicted with dignity and confidence. While Louie's reaction to her identity is one of internal discomfort, the narrative does not mock or denigrate Vanessa. The portrayal is brief and serves to explore Louie's personal biases, resulting in a neutral overall impact on trans themes.

The show frequently portrays Christianity through characters who are hypocritical, judgmental, or dogmatic, often satirizing the rigidities and perceived absurdities of organized religion. Louie's personal skepticism and the narrative's framing often highlight the flaws rather than the virtues of the faith.