Reservation Dogs offers a positive portrayal of LGBTQ+ characters. Respected lesbian elder Teenie and the fondly remembered gay character Daniel are integrated naturally into the narrative. The show depicts an Indigenous community that is generally accepting of diverse identities, presenting LGBTQ+ individuals with dignity and complexity without their identity being a source of ridicule or conflict.

Reservation Dogs features Auntie B, a Two-Spirit character portrayed with dignity and respect as a wise elder and spiritual guide. Her identity is seamlessly integrated into the narrative as an accepted aspect of Indigenous culture, serving as a positive influence without being a source of conflict or ridicule. The show affirms the worth of such identities through her complex and valued presence.

The show frequently satirizes the performative aspects and hypocrisy of Christian institutions and some adherents within the Indigenous community, often contrasting it with the more authentic portrayal of traditional beliefs and highlighting its colonial legacy.