NYPD Blue featured Detective John Irvin, a recurring gay character whose arc explored his coming out and professional life with dignity. While facing initial prejudice, the show ultimately depicted his identity and relationships with empathy and complexity, framing obstacles as external and affirming the worth of LGBTQ+ lives within a realistic police drama context.

NYPD Blue featured transsexual characters, notably in an episode depicting a trans woman as a victim of a hate crime. While the narrative condemned the violence and sought justice, reflecting an empathetic stance, the portrayal also included problematic elements common for its era, such as the character's tragic circumstances, sex worker stereotype, and misgendering by some characters. The net impact is neutral, as the show's positive message against prejudice is balanced by these problematic depictions.

The series frequently explores Christian themes through its characters' moral struggles, redemption arcs, and cultural backgrounds, often portraying faith as a source of comfort, guidance, or personal conflict. While individual hypocrisy is depicted, the narrative consistently critiques these failings rather than condemning the faith itself, treating Christian belief with nuance and respect for its role in human experience.

The series includes Muslim characters and communities, portraying their faith and cultural identity with a focus on individual experiences and human complexity. The narrative avoids broad generalizations, instead presenting Islam as a diverse belief system within the city, treated with respect and realism.

Judaism is depicted as an integral part of New York City's diverse cultural and religious landscape, often through victims, witnesses, or supporting characters. The show portrays Jewish individuals and their practices with realism and nuance, focusing on human stories without endorsing negative stereotypes or condemning the faith.