Dern is known as an outspoken activist and supporter of many charitable causes, such as Healthy Child Healthy World, which aims to raise awareness about toxic substances that can affect a child's health. She has been acknowledged with several awards from the independent film industry including the Sundance Institute and was the subject of an aggressive media campaign by David Lynch to win her an Academy Award nomination for her work in Inland Empire.

Dern had high-profile romances with Kyle MacLachlan, Nicolas Cage, Renny Harlin, Jeff Goldblum, and Billy Bob Thornton (who ended their relationship abruptly by marrying Angelina Jolie). She married musician Ben Harper on December 23, 2005, after dating him for five years. She has two children, son Ellery (born 21 August 2001) and daughter Jaya (28 November 2004).