Carradine's first television appearance was in 1971, on the classic western series, Bonanza. He also appeared on his brother David's series, Kung Fu, as Sunny Jim, the mute companion of Serenity Johnson, played by his Father, John, in an episode called Dark Angel (1972). In 1979, he was alongside Melissa Sue Anderson in Survival of Dana. In 1984, Carradine played Robert Cohn in the television mini-series version of Ernest Hemingway's The Sun Also Rises. He appeared in the 1987 HBO mini-series, Conspiracy: The Trial of the Chicago 8. He was also a guest star in an episode of Law & Order: Criminal Intent entitled Gone (2005, Season 4, Episode 11). He also took part in Jane Doe, a TV series directed by James A. Contner, in 2007.

Carradine made his film debut in 1972 in The Cowboys with John Wayne. He was also featured in a short-lived television series, of the same name, based on the movie. He made an appearance as a killer in the Martin Scorsese film Mean Streets shooting to death the character played by his brother, David.

During this time he worked with David on some independent projects including a biker film called You and Me (1975) and an unreleased musical called A Country Mile. He also did camera work for David's cult classic Vietnam War-inspired Americana which was not released until 1983.

In 1976, Carradine had the opportunity to demonstrate on screen what he considered to be his "first ambition", car racing, when he played Jim Cantrell in Paul Bartel's Cannonball. In the film Robert's character ironically wins the cross country road race, beating the favorite, Coy "Cannonball" Buckman, played by his brother, David. In 1977, Robert became a snack for the vengeful killer whale in the Jaws imitation film Orca.

In 1978, Robert landed a demanding role in Hal Ashby's Oscar-winning Vietnam War drama, Coming Home, which starred Jane Fonda and Jon Voight. His performance caused some speculation that he might be the best actor in his family.

Also in 1980, Carradine co-starred with Mark Hamill and Lee Marvin in Samuel Fuller's The Big Red One recounting Fuller's WW II experience. His character, who was based on Fuller himself, narrated the film.

In 1983, he and Cherie Curie starred in the science fiction movie Wavelength in which he played a washed up rock star who helps extraterrestrials escape from a military base. For the film he performed his own compositions including one named after his daughter, Ever. Also in 1983, he starred in the music video for The Motels hit song "Suddenly Last Summer" as lead singer Martha Davis' love interest.

Carradine's biggest film success to date came in 1984 when he starred in Revenge of the Nerds as the lead nerd Lewis Skolnick. To prepare for the comedy, Carradine spent time at The University of Arizona, where the movie was filmed, participating in rush week. "No fraternity picked him, convincing Carradine that he was indeed right for the part of the nerd that nobody wanted to claim as their own." Carradine reprised the role of Skolnick in three sequels, taking over as executive Producer in the latter two. In 2001 he played Donald Keeble in Max Keeble's Big Move. In 2000 he co-starred with Caroline Rhea in Mom's Got a Date with a Vampire. He reprised his role as Sam McGuire in The Lizzie McGuire Movie in 2003.

In January 2013, he and former Revenge of the Nerds co-star, Curtis Armstrong, hosted King of the Nerds, a reality TV series in which a group of nerds compete to find out which one is the nerdiest.

TMZ reported on March 12, 2015 that Carradine was involved in a serious car accident. He was rushed to the hospital. His wife was also injured in the crash.