St. Elsewhere was a trailblazer in its empathetic and complex portrayal of LGBTQ+ characters and themes, particularly during the early AIDS epidemic. It depicted gay characters with dignity, highlighting external societal prejudices and the devastating impact of AIDS, while generally affirming the worth of LGBTQ+ lives.

St. Elsewhere featured Dr. Roxanne Turner, a transsexual surgeon, in a groundbreaking portrayal for 1980s television. The character was depicted with dignity and professional competence. While the show explored other characters' initial reactions and prejudices, it framed these as external obstacles. The narrative ultimately affirmed Dr. Turner's worth and identity, contributing to a net positive impact on transsexual representation.

The show frequently depicted characters of various Christian faiths, exploring their beliefs, doubts, and moral dilemmas with nuance. While individual adherents might be flawed, the narrative generally treated Christian faith as a significant and complex aspect of characters' lives, often a source of comfort or ethical guidance, without condemning the religion itself.

Jewish characters and cultural practices were integrated into the hospital's diverse environment, often highlighting their personal and communal significance during times of crisis. The narrative portrayed Judaism with respect, focusing on the human experience within the faith rather than offering a critical or negative stance.