"Nurse Jackie" features multiple LGBTQ+ characters, including Dr. Roman and Thor Lundgren, whose same-sex relationships are depicted as stable and normalized. These characters are portrayed with dignity and professionalism, integrating their identities respectfully into the narrative without relying on stereotypes or making their orientation a source of conflict. The overall portrayal is affirming and validating.

Nurse Jackie features a trans woman character who is depicted as a supportive and wise AA sponsor. Her trans identity is handled with dignity and respect, portraying her as a well-adjusted individual whose presence positively contributes to the protagonist's journey without relying on harmful stereotypes.

The series portrays Catholicism with nuance, exploring how characters like Jackie struggle with its tenets while others, like Zoey, find genuine comfort and guidance in their faith. The narrative treats the religion as a complex, integral part of its characters' lives, rather than condemning it or its institutions.