A member of the Actors Studio, he rose to prominence during the New Hollywood era through roles in films such as The Trip (1967), They Shoot Horses, Don't They?

Other notable films include The Laughing Policeman (1973), The Great Gatsby (1974), Posse (1975), Family Plot (1976), Black Sunday (1977), The Driver (1978), Tattoo (1981), That Championship Season (1982), The 'Burbs (1989), Last Man Standing (1996), Monster (2003), Down in the Valley (2005), Chappaquiddick (2017), and Emperor (2020).

Dern's maternal grandfather was a Vice President of the Carson, Pirie and Scott stores,[8][9] which were established by his own father, Scottish-born businessman Andrew MacLeish.

He played a murderous rustler in Hang 'Em High, a gunfighter in Support Your Local Sheriff!, and an impoverished farmer in the film adaptation of Horace McCoy's novel They Shoot Horses, Don't They?.

Dern had a leading role in the ecological science-fiction film Silent Running and co-starred with Jack Nicholson in The King of Marvin Gardens.

In Kirk Douglas' Revisionist Western film Posse, Dern played a train-robber who uses his wiles to turn the tables on his captor, an ambitious, politically minded marshal.

In John Frankenheimer's thriller film Black Sunday, Dern played a vengeful Vietnam War veteran and Goodyear Blimp pilot who launches a massive terrorist attack at the Super Bowl.

Dern played another Vietnam veteran and the disturbed husband of a perplexed woman (Jane Fonda) in Hal Ashby's war film Coming Home, and was nominated for an Academy Award for Best Supporting Actor.

However, he bounced back by winning the Silver Bear for Best Actor at the 33rd Berlin International Film Festival for his performance in Jason Miller's That Championship Season (1982).

[12][13] In the course of his long and prolific career, Dern collaborated with film directors, including Walter Hill (The Driver, Wild Bill and Last Man Standing), Joe Dante (The 'Burbs, Small Soldiers and The Hole), and Quentin Tarantino (Django Unchained, The Hateful Eight and Once Upon a Time in Hollywood).

Club, Dern said: "I always say that I feel like I've worked for six geniuses in my career... And the six directors, not in any order, would be Mr. Kazan, Mr. Hitchcock, Douglas Trumbull, Alexander Payne, Quentin Tarantino, and Francis Coppola.