Cardellini was born in Redwood City, California, the daughter of Lorraine (née Hernan), a homemaker, and Wayne David Cardellini, a businessman. She is the youngest of four children. Cardellini is of Italian, Irish, German, and Scottish descent. She was raised Catholic. She made her first public appearance at age 10, when she sang in a school play. Subsequently, she acted in several school productions and started attending drama lessons. She graduated from nearby Mountain View's Catholic St. Francis High School in 1993, then moved to Los Angeles to seek roles in television and film.