The show "Big Mouth" features multiple prominent LGBTQ+ characters, including Matthew (gay), Jay (bisexual), and Ali (pansexual). Their identities are explored with nuance, contributing significantly to their character development. While the show uses crude humor, it generally portrays these characters and their experiences with empathy and affirmation, particularly through Matthew's coming-out journey and Jay's self-discovery.

Big Mouth introduces Natalie, a trans girl, whose portrayal is affirming. The narrative respectfully depicts her finding acceptance among peers, addressing her identity with dignity and empathy, and framing challenges as learning opportunities for allyship.

The show frequently features Jewish characters and cultural practices, such as bar mitzvahs and holidays. While often the subject of comedic situations and character neuroses, the portrayal is generally affectionate, normalizing, and explores the complexities of identity within a Jewish cultural context without condemning the faith itself.