American Dad! incorporates LGBTQ+ characters and themes primarily through Roger's fluid identities and specific plotlines. These elements are generally used for comedic effect, presenting queer identities as incidental to the show's irreverent humor rather than offering explicit affirmation or degradation. The portrayals avoid strong positive or negative arcs, resulting in a neutral net impact.

American Dad! features a significant transsexual character arc in the episode "Tuttle's Rehab," where Tuttle comes out as Trixie, a trans woman. While presented with the show's characteristic humor, the narrative ultimately supports Trixie's journey of self-acceptance and living authentically, with Stan becoming an ally. The portrayal is affirming of trans identity.

The show frequently satirizes the hypocrisy, bigotry, and self-righteousness of characters who identify as Christian, particularly Stan Smith. While satirical, the narrative often links these negative traits to the adherents' (often superficial) faith, reinforcing a problematic portrayal.

American Dad! often critiques Islamophobia and xenophobia, particularly through Stan's initial prejudices which are frequently challenged and proven wrong by the narrative. The show positions the audience to sympathize with Muslim characters and condemn bigotry against them.