American Gods features a prominent and affirming portrayal of a gay relationship through Salim and the Jinn. Their love story is depicted with complexity, dignity, and mutual respect, contributing significantly to a positive net impact for LGBTQ+ representation in the series.

The character Mr. World, established as male in the source novel, is portrayed in the show by multiple actors, including a female actor as "Ms. World," explicitly presented as another manifestation of the same character.

Shadow Moon, canonically described as half-white and half-Native American in the source novel, is portrayed by an actor of Black and white heritage in the show, constituting a race swap.

The series critically explores the decline of Christian faith, the hypocrisy of some adherents, and the historical violence associated with its spread. It portrays Christianity struggling for relevance against modern 'New Gods,' often highlighting its problematic aspects.