Desperate Housewives features prominent LGBTQ+ characters whose arcs are largely affirming. Andrew Van de Kamp's journey to self-acceptance and his mother's eventual embrace, alongside the stable and loving portrayal of Bob and Lee, demonstrates a net positive impact. The show depicts challenges but ultimately validates queer lives and relationships.

Desperate Housewives features a transsexual character, Rebecca, whose identity is revealed as a shocking secret. This revelation leads to her immediate rejection by a cisgender love interest, Mike, who feels deceived. The narrative frames her identity as a source of betrayal and discomfort, without challenging the cisgender character's negative reaction, contributing to a problematic portrayal.

The show critiques the hypocrisy and judgmentalism of individuals within a suburban Christian community, often satirizing the gap between professed faith and actual behavior. However, the narrative consistently positions the audience to condemn this bigotry, while also depicting characters who genuinely grapple with moral dilemmas rooted in their faith, ultimately affirming the underlying virtues of the religion.