The series features Holly Gibney, a character whose traits align with asexuality, though this identity is not explicitly stated or central to the plot. Her portrayal is complex, focusing on her intellect and social anxieties, without her sexual orientation being a source of affirmation or denigration. The depiction is incidental, neither uplifting nor problematic.

Mr. Mercedes features Ida Silver, a transgender woman, in a supporting role as a librarian and friend. Her trans identity is present but incidental to the main narrative, neither uplifting nor denigrating. The portrayal is neutral, presenting her as an ordinary character without significant focus on her gender identity as a source of conflict or affirmation.

In the source novel, Jerome Robinson's mother, Barbara Robinson, is Black. In the 2017 show, the character is portrayed by a white actress, Ann Cusack, constituting a race swap.

The series portrays Deborah Hartsfield's Catholicism as deeply intertwined with her mental illness, guilt, and abusive behavior, directly contributing to her son Brady's psychological damage. Her use of religious concepts is depicted as hypocritical and twisted, serving as a significant negative influence without counterbalancing positive portrayals of the faith within the narrative's focus.