Harry Stanton appeared in indie and cult films (Two-Lane Blacktop, Cockfighter, Escape from New York, Repo Man), as well as many mainstream Hollywood productions, including Cool Hand Luke, The Godfather Part II, Alien, Red Dawn, Alpha Dog, Pretty in Pink, Stephen King’s Christine and The Green Mile. He was a favorite actor of Sam Peckinpah, John Milius, David Lynch, and Monte Hellman, and was also close friends with Francis Ford Coppolaand Jack Nicholson, he was best man at Nicholson’s wedding in 1962. He made his first television appearance in 1954 in Inner Sanctum and made his film debut three years later in the Western Tomahawk Trail. He appeared (uncredited) as a complaining BAR man in the very beginning of the Gregory Peck film Pork Chop Hill in 1959. He had a very small part in 1962’s How The West Was Won as one of Charlie Gant’s (Eli Wallach) gang, and followed that with a minor role as a poetry-reciting beatnik in the Danny Kaye film The Man from the Diner’s Club in 1963. Early in his career he took the name Dean Stanton to avoid confusion with the actor Harry Stanton. His breakthrough part came with the lead role in director Wim Wenders’ film Paris, Texas (1984). Playwright Sam Shepard, the movie’s screenwriter, had spotted Stanton at a bar in Santa Fe, New Mexico, in 1983 while both were attending a film festival in that city, and the two fell into conversation. “I was telling him I was sick of the roles I was playing,” Stanton recalled in a 1986 interview. “I told him I wanted to play something of some beauty or sensitivity. I had no inkling he was considering me for the lead in his movie.” Not long afterward, Shepard phoned him in Los Angeles to offer Stanton the part of protagonist Travis, “a role that called for the actor to remain largely silent … as a lost, broken soul trying to put his life back together and reunite with his estranged family after having vanished years earlier.”

Stanton was a favorite of film critic Roger Ebert, who said that “no movie featuring either Harry Dean Stanton or M. Emmet Walsh in a supporting role can be altogether bad.” However, Ebert later admitted that Dream a Little Dream (1989), in which Stanton appeared, was a “clear violation” of this rule. His television credits were extensive, including eight appearances between 1958 and 1968 on CBS’s Gunsmoke, four on the network’s Rawhide, two on Bonanza and an episode of The Rifleman as well as a cameo in Two and a Half Men (having previously appeared with Jon Cryer in Pretty in Pink and with Charlie Sheen in Red Dawn), alongside Sean Penn and Elvis Costello. He was featured beginning in 2006 as Roman Grant, the manipulative leader/prophet of a polygamous sect on the HBO television series Big Love. He also played Henry in an episode of the television series Adam-12. Harry Stanton also occasionally toured nightclubs as a singer/guitarist, playing mostly country-inflected cover tunes. He appeared in the Dwight Yoakam music video for “Sorry You Asked”, portrayed a cantina owner in a Ry Cooder video for “Get Rhythm”, and participated in the video for Bob Dylan’s “Dreamin’ of You”. He worked with a number of musical artists such as Dylan, Art Garfunkel and Kris Kristofferson and provided harmonica on The Call’s 1989 album Let the Day Begin.

During 2010, Harry Stanton appeared on the NBC show Chuck for one episode, reprising his role as a repo man from the 1984 film Repo Man. In 2011, the Lexington Film League created an annual festival, the Harry Dean Stanton Fest, to honor Stanton in the city where he spent much of his adolescence. In 2012, he had brief cameos in The Avengers and in the action comedy Seven Psychopaths. He also had a brief role in the Arnold Schwarzenegger action film The Last Stand (2013). Stanton was the subject of a 2013 documentary titled Harry Dean Stanton: Partly Fiction, directed by Sophie Huber and featuring film clips; interviews with collaborators including Wenders, Shepard, Kris Kristofferson, and David Lynch; and Stanton’s singing. In 2017, he was featured in the Showtime limited series Twin Peaks: The Return, a continuation of David Lynch’s 1990–91 television series. He reprised his role as Carl Rodd from Twin Peaks: Fire Walk With Me. He played his ultimate (leading) role in the 2017 film Lucky, John Carroll Lynch’s directorial debut.