The show features multiple LGBTQ+ characters, including a bisexual king and a lesbian lady-in-waiting. Their relationships are portrayed with dignity and complexity, contributing to the historical court's social fabric without being sensationalized or denigrated. The narrative maintains a respectful and empathetic stance toward queer identities, framing any challenges as external societal pressures.

The Serpent Queen features Angelica, a trans woman, as a respected and trusted member of Catherine de' Medici's court. Her identity is acknowledged without judgment or mockery, and she is portrayed with dignity and skill, contributing to a net positive and affirming depiction of a trans character.

Louis de Bourbon, Prince of Condé, a historical French nobleman of European descent, is portrayed by Ray Panthaki, an actor of Indian descent. This constitutes a race swap for a significant historical character.

The series consistently portrays Christianity, specifically the conflict between Catholic and Protestant factions, as a primary driver of political manipulation, hypocrisy, and brutal violence. The narrative uses dark humor and Catherine's cynical perspective to highlight the destructive consequences of religious intolerance and the self-serving actions of those in power who exploit faith. It critiques the institutional and political manifestations of religion rather than individual faith.