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 frequently portrays Christian characters as hypocritical, judgmental, or using their faith as a social tool rather than a genuine moral compass. The narrative often critiques the flawed application of religious principles, highlighting the gap between outward piety and inner turmoil or secret sins, reinforcing a problematic view of how religion functions in this community.