She is known for her collaborations with filmmaker David Lynch, having appeared in three of his films, and the upcoming revival of Twin Peaks.
Dern was born in Los Angeles, California, the daughter of actress Diane Ladd and actor Bruce Dern, and great-granddaughter of former Utah governor and Secretary of War, George Dern; Dern was conceived while her parents were filming The Wild Angels.
In October 2011, Dern starred in a new HBO television series called Enlightened.
Dern plays Amy Jellicoe, "a health and beauty executive who returns from a post-meltdown retreat to pick up the pieces of her broken life" with, among others, her mother, played by her real-life mother Ladd.
She guest-starred on The West Wing, was a voice on King of the Hill, and was a lesbian who coaxes Ellen De Generes out of the closet in the famous 1997 "The Puppy Episode" of the television series Ellen.
On the April 24, 2007, airing of De Generes's talk show, Dern revealed she did not work for more than a year following her appearance in that episode because of resulting backlash, but nevertheless called it an "extraordinary experience and opportunity." Dern 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's starring role in Blue Velvet was a breakthrough though her next notable film, Wild at Heart, took almost four years to be released.