Majors' best-known role before Steve Austin was in The Big Valley, a 1960s series with the late screen legend Barbara Stanwyck. In later years, he starred in another popular series, The Fall Guy (1981-86), as "Colt Seavers", a Hollywood stunt- man who works as a bounty hunter when stunt work is slow. One of television's most durable actors, Majors also starred in many other TV series including The Big Valley (as Heath Barkley, 1965-69), The Virginian (1970-71), Owen Marshall: Counselor at Law (1971-74), Tour of Duty (1990), Raven (1992-93), and Too Much Sun (2000). He received critical acclaim for his performance in the 1969 made-for-TV film, The Ballad of Andy Crocker. In the 1980s and 1990s, he reprised his most famous role in three The Six Million Dollar Man/The Bionic Woman reunion TV-movies, with actress Lindsay Wagner.

Majors has been married four times, but his most famous marriage was to actress Farrah Fawcett, another huge 1970s pop icon. In 1976 Majors and Fawcett made TV history by being a husband and wife each starring in separate top rated shows, The Six Million Dollar Man (Majors) and Charlie's Angels (Fawcett). They were married from July 28, 1973 to February 16, 1982, but they separated in 1979. They broke up because Majors wanted his spouse to be home with him in the evenings when she often needed to work on her show. The producers of her show made some concessions—for example she was allowed to leave the set to prepare dinner for Majors every evening—but eventually the demands of both their careers proved too onerous and they parted ways.

Majors has four children from two of his marriages. He has one son, actor Lee Majors II (born circa 1962), from his marriage to Kathy Robinson (1961 - 1964), who would go on to appear as an OSI agent in the three The Six Million Dollar Man/The Bionic Woman reunion movies with his father. His marriage to former Playboy Playmate, Karen Velez (1988 - 1994) produced one daughter, Nikki Majors, and twin sons, Dane Majors and Trey Majors. He is currently married to Faith Noelle, whom he wed on November 1, 2002.

Majors continues to play roles in made for TV movies and makes cameo appearances on other shows and TV commercials, occasionally parodying his Steve Austin image.

A cartoon image of Majors and later, a reference to the The Six Million Dollar Man, appears in the "Running Mates" episode of the television series Family Guy.