The show features Juan Borgia, a prominent antagonist, whose implied bisexuality/homosexuality is consistently linked to his depravity, cruelty, and moral decay. His same-sex relationships are used to underscore his villainous character, presenting a problematic portrayal that associates queer identity with moral corruption without counterbalance or positive framing.

The series consistently portrays the Roman Catholic Church, particularly its highest echelons during the Borgia papacy, as deeply corrupt, hypocritical, and driven by worldly power, greed, and lust. The narrative exposes the moral failings of its leaders, including Pope Alexander VI, without significant counterbalancing positive portrayals of the institution itself.

Jewish characters are generally depicted with dignity, resilience, and intelligence, often as victims of Christian persecution. The narrative implicitly critiques the anti-Semitism of the era rather than the Jewish faith itself.