The Big C features Sean, Cathy's openly gay brother, as a significant and complex character. His identity is portrayed with dignity, and his loving relationship is normalized. The show avoids stereotypes and does not make his sexuality a source of ridicule or tragedy, resulting in a net positive and affirming depiction of LGBTQ+ identity.

The Big C features Dr. Todd Mauer, a trans man whose transition is a significant character arc. The show portrays his journey with dignity and agency, and the protagonist's eventual acceptance highlights an empathetic and supportive narrative toward transgender identity.

The show portrays individual Christian faith with sincerity and as a source of comfort and community, even while critically examining the rigidity or hypocrisy of religious institutions and dogma. The narrative explores the human struggle with faith and doubt, positioning questioning as a valid and empathetic response to mortality.