Duvall was an artistic and energetic young child, eventually earning the nickname “Manic Mouse” from her mother. She also became interested in science at a young age, and as a teenager aspired to become a scientist. After graduating from Waltrip High School in 1967, Duvall sold cosmetics at Foley’s and attended South Texas Junior College, where she majored in nutrition and diet therapy.

Duvall married artist Bernard Sampson in 1970. Around this time, she met Robert Altman at a party while he was shooting Brewster McCloud (1970) on location in Texas. Several crew members for the film were fascinated by Duvall’s upbeat presence and unique physical appearance, and asked her to be part of the feature. Duvall reflected on committing to the project: “I got tired of arguing, and thought maybe I am an actress. They told me to come. I simply got on a plane and did it. I was swept away.” Duvall had never left Texas before Altman offered her the film role. She flew to Hollywood and subsequently appeared as the free-spirited love interest to Bud Cort’s reclusive Brewster in Brewster McCloud.

Altman subsequently chose Duvall for roles as an unsatisfied mail-order bride in McCabe & Mrs. Miller (1971), and the daughter of a convict and mistress to Keith Carradine’s character in Thieves Like Us (1974). Duvall’s marriage to Sampson disintegrated as her acting career accelerated, and they divorced in 1974. Next, Duvall appeared as a spaced-out groupie in Altman’s ensemble comedy Nashville (1975), and a sympathetic Wild West woman in Buffalo Bill and the Indians, or Sitting Bull’s History Lesson (1976).

In 1977, Duvall starred as Mildred “Millie” Lammoreaux in Altman’s psychological thriller 3 Women, portraying a woman living in a dreary California desert town. Duvall’s performance garnered the award for Best Actress at the 1977 Cannes Film Festival and the LAFCA Award for Best Actress, as well as a BAFTA nomination. She next appeared in a minor role in Woody Allen’s Annie Hall (1977). While she was shooting Annie Hall in New York, Duvall met singer/songwriter Paul Simon. The couple began a relationship and lived together for two years. Their relationship ended when Duvall introduced Simon to her friend, actress Carrie Fisher; Fisher took up with Simon.

Her role of Pansy in Terry Gilliam’s Time Bandits (1981) followed. Shortly before the release of the film, it was reported that Duvall and actor Stanley Wilson (who portrayed the town barber in Popeye) were set to marry. However, no further reports were released regarding this. In 1982, Duvall narrated, hosted and was executive producer of the children’s television program Faerie Tale Theatre. She starred in seven episodes of the series; “Rumpelstiltskin” (1982), “Rapunzel” (1983), “The Nightingale” (1983), “Snow White and the Seven Dwarfs” (1984), “Puss in Boots” (1985), and “Aladdin and His Wonderful Lamp” (1986). Since the program’s first episode “The Frog Prince”, which starred Robin Williams and Teri Garr, Duvall produced 27 hour-long episodes of the program. In 1985, she created Tall Tales & Legends, another one-hour anthology series for Showtime, which featured adaptations of American folk tales. As with Faerie Tale Theatre, the series starred well-known Hollywood actors with Duvall as host, executive producer, and occasional guest star. The series ran for nine episodes and garnered Duvall an Emmy nomination.

In 1988, Duvall founded a new production company called Think Entertainment to develop programs and television movies for cable channels. She created Nightmare Classics (1989), a third Showtime anthology series that featured adaptations of well-known horror stories by authors including Edgar Allan Poe. Unlike the previous two series, Nightmare Classics was aimed at a teenage and adult audience. It was the least successful series that Duvall produced for Showtime and ran for only four episodes.

In 1991, Duvall portrayed Jenny Wilcox, wife of Charlie Wilcox (Christopher Lloyd) in the Hulk Hogan action-adventure film Suburban Commando. In October that year, Duvall released two compact discs, Hello, I’m Shelley Duvall… Sweet Dreams that features Duvall singing lullaby songs and Hello, I’m Shelley Duvall… Merry Christmas, on which Duvall sings Christmas songs.

While Duvall was producing Faerie Tale Theatre, it was reported that she was to star as the lead in the film adaptation of Tom Robbins’s Even Cowgirls Get the Blues, which starred Mick Jagger, Jerry Hall, her sister Cindy Hall and Sissy Spacek. The project was delayed and when finally released in 1993, starred an entirely different cast. She also landed roles in films and television series: the mother of a boy whose dog is struck by car in Tim Burton’s short film Frankenweenie (1984), and as Laura Burroughs in Booker (also 1984), a biographical television short based on the life of Booker T. Washington, directed by Stan Lathan. Next, Duvall appeared a lonely and timid woman who receives a message from a flying saucer in The Twilight Zone episode “The Once and Future King/A Saucer of Loneliness”, and the friend of Steve Martin’s character in the comedy Roxanne (1987).

The following year, Think Entertainment joined the newly formed Universal Family Entertainment to create Duvall’s fourth Showtime original series, Shelley Duvall’s Bedtime Stories, which featured animated adaptations of children’s storybooks with celebrity narrators and garnered her a second Emmy nomination. Duvall produced a fifth series for Showtime, Mrs. Piggle Wiggle, before selling Think Entertainment in 1993 and retiring as a producer. Duvall’s production work gained her six CableACE Awards and one Peabody Award. A year later, Duvall landed a guest spot on the television series L.A. Law as Margo Stanton, a show dog owner and breeder who presses charges against the owner of a Welsh Corgi that mated with her prize-winning Afghan Hound.

After the 1994 Northridge earthquake, Duvall relocated from her Benedict Canyon, Los Angeles home to Blanco, Texas. She subsequently appeared as the vain, over-friendly, but harmless Countess Gemini—sister to the calculating Gilbert Osmond (John Malkovich)—in Jane Campion’s 1996 adaptation of the Henry James novel The Portrait of a Lady. A year later, she played a beatific nun in the comedy film Changing Habits and a besotted, murderous, ostrich-farm owner in Guy Maddin’s fourth feature Twilight of the Ice Nymphs. The same year she played Chris Cooper’s character’s gullible wife who yearns for a better life in Horton Foote’s made-for-television film, Alone. Duvall continued to make film and television appearances throughout the late-1990s. In 1998, she played Drew Barrymore’s mother in the comedy Home Fries and Hilary Duff’s aunt in the direct-to-video children’s film Casper Meets Wendy. Near the end of the decade, she returned to the horror genre with a minor roles in Tale of the Mummy (1998), co-starring Christopher Lee and Gerard Butler, and The 4th Floor (1999), co-starring Juliette Lewis.

In the 2000s, Duvall accepted minor roles, including the mother of Matthew Lawrence’s character in the horror-comedy Boltneck (2000) and Haylie Duff’s aunt in the independent family film Dreams in the Attic, which was sold to the Disney Channel but was never released. Her most recent acting appearance was a small role in the 2002 independent film Manna from Heaven.

Duvall has lived out of public view since her retirement in 2002. In November 2016, USA Today reported that she appeared to be suffering from mental illness. A segment featuring Duvall on Dr. Phil in 2016 drew significant criticism from the public, with many suggesting that Shelley Duvall’s mental illness was being exploited. In the segment, she refused the offered treatment.