She was born as Robert Arquette in Los Angeles, California, the fourth of five children of Brenda Olivia "Mardi" (née Nowak), an actor, poet, theater operator, activist, acting teacher, and therapist, and Lewis Arquette, an actor and director. Mardi was Jewish. Lewis's family's surname was originally "Arcouet" of partial French-Canadian ancestry; Lewis's father was comedian Cliff Arquette, who went by the stage name of Charley Weaver. Alexis Arquette was distantly related to American explorer Meriwether Lewis. Actors Rosanna, Richmond, Patricia, and David Arquette were her siblings.