House of Lies features a main character, Doug Guggenheim, who is gay. His sexuality is presented as a normal aspect of his identity and relationships, neither serving as a primary source of conflict nor as a central theme for explicit affirmation or denigration. The portrayal is largely incidental.

The show features a trans woman character, Lex, who is portrayed with dignity and agency. While a cisgender character initially reacts with shock and discomfort to her identity, the narrative explores and challenges this prejudice, ultimately affirming Lex's worth and identity.

The show's protagonist, Marty Kaan, is a fictionalized version of the real-life author Martin Kihn, who is white. Marty Kaan is portrayed by a Black actor, constituting a race swap for a character based on a documented historical figure.

The show frequently satirizes characters who profess Christian values but act hypocritically, using their faith as a facade for self-serving or unethical corporate behavior. The narrative offers no significant counterbalancing positive portrayals, reinforcing a critical view of how religion is practiced in this environment.