Griffith has been married four times. She was wed to the actor Don Johnson briefly in 1976. She later wed actor Steven Bauer in September 1981, but divorced in 1987. In 1989 Griffith married Johnson again, but the pair split several years later and the divorce was finalized just before Griffith married her current husband, Antonio Banderas, whose name she has tattooed on her arm, in May 1996.

Griffith has three children, one with each of her three husbands: Alexander Griffith Bauer (born in 1985), Dakota Mayi Johnson (born in 1989), and Stella del Carmen Griffith Banderas (born in 1996). Dakota followed in her mother's footsteps and served as Miss Golden Globe at the 2006 Golden Globes awards ceremony. Griffith herself was Miss Golden Globe in 1975.