The Cleveland Show features LGBTQ+ characters, notably the openly gay and married Terry Kimple, offering some representation. However, the show frequently utilizes LGBTQ+ stereotypes for comedic purposes, often through incidental gags. This blend of stable representation and stereotypical humor results in a net neutral impact on the portrayal of queer identity.

The Cleveland Show features a transsexual character, Cookie, in one episode. The narrative explores the discomfort and eventual, albeit reluctant, acceptance of her identity by her son, Holt. While some humor arises from the situation and initial reactions are problematic, the episode ultimately critiques prejudice and does not portray the trans character as inherently negative or solely for ridicule.

The show frequently satirizes Christian practices, institutions, and adherents, often highlighting hypocrisy, dogmatism, and the comedic absurdity of certain beliefs. Its humor often derives from portraying religious figures or situations as foolish or misguided, reinforcing a critical view rather than affirming the faith's virtues.