Rescue Me offers a largely positive portrayal of LGBTQ+ characters. Mike Siletti's coming-out arc is handled with empathy, showing his journey of self-acceptance and eventual integration. Maggie Gavin's lesbian identity is depicted as a natural part of her complex character, with her relationships treated with the same dramatic depth as others, affirming the worth of queer lives within the show's gritty world.

Rescue Me includes a storyline where firefighter Mike Siletti dates a transsexual woman, Maggie. The plot primarily explores Mike's initial shock and the subsequent transphobic reactions, jokes, and slurs from his colleagues. While Mike eventually reconciles with Maggie, the pervasive use of harmful stereotypes and ridicule by other characters, often for comedic effect, results in a problematic portrayal of trans identity.

The show deeply explores the struggles and complexities of Catholic faith among its characters, particularly in the face of trauma and grief. While characters express doubt and anger, the narrative treats the religion with respect, highlighting its role in community, coping, and personal identity without condemning the faith itself.