After turning down an offer to play professional baseball to pursue an acting career, Majors relocated to Hollywood in the early 1960s armed with an education degree and a boyhood adoration of James Dean. While working as a recreation director for the Los Angeles parks department, he met numerous individuals involved with show business and was able to secure a shot at studying acting at MGM. Dick Clayton, who had been James Dean's agent, took Majors on and got him his "big break". The role was Heath, the product of an extra-marital liaison by the deceased husband of Victoria Barkley (Barbara Stanwyck) whom she nevertheless made a full-fledged member of the family on "The Big Valley" (ABC, 1965-69). Majors and fellow neophyte co-star Linda Evans emerged as rising TV stars.

Although the actor stumbled a bit with his next series, "The Men From Shiloh" (NBC, 1970-71), a revamped version of the popular Western "The Virginian", he continued to find work. His rugged good looks and solid presence led to his casting as the second-seat lawyer to "Owen Marshall: Counselor at Law" (ABC, 1971-74). By 1973, he was simultaneously appearing in two series, having landed the role of Colonel Steve Austin, "The Six Million Dollar Man" (ABC, 1973-1978), a military hero who had been reconstructed as a cyborg, the half-man, half-robotic invention. After a slow start, the series grew into one of the network's most popular, spawning a female counterpart (Lindsay Wagner's "The Bionic Woman") who was eventually spun-off into her own series. Majors and Wagner frequently reprised these roles in a series of TV-movies since the late 80s.

Majors became a frequent guest on variety series during the late 70s before trying his hand at another series, "The Fall Guy" (ABC, 1981-85), in which he portrayed a stuntman who also worked as a bounty hunter. He not served as the show's executive producer but also performed the theme song. After a recurring role on the Vietnam drama series "Tour of Duty" (CBS, 1990), Majors returned to regular work with the short-lived CBS drama "Raven" (1992), as a CIA operative turned private eye.

Since the late 60s, Majors has also found employment in TV longforms. His debut was as a returning soldier who returns to find his wife remarried in one of the first TV-movie to focus on Vietnam veterans in "The Ballad of Andy Crocker" (ABC, 1969). He was a kidnapper holding nuns hostage in "Weekend of Terror" (ABC, 1970) and acquitted himself in the title role as "Francis Gary Powers: The True Story of the U-2 Spy Incident" (NBC, 1976). Majors again was a Vietnam veteran, this time assisting in the rehabilitation of his injured friend (James Stacy), in "Just a Little Inconvenience" (NBC, 1977) and assumed the role Will Kane, (originated by Gary Cooper) in the 1980 CBS TV-movie "High Noon, Part II: The Return of Will Kane". In addition to his numerous reprisals as "The Six Million Dollar Man" in longforms, more recently he was among those searching for missing gold in "The Lost Treasure of Dos Santos" (The Family Channel, 1997).

On the big screen, the actor made his feature debut, billed under his real name of Lee Yeary in "Straight-Jacket" (1964) and his subsequent work has been sporadic. He co-starred as a thug stalking Charlton Heston in "Will Penny" (1968) and also appeared in "The Liberation of L.B. Jones" (1970) as well as numerous low-budget action films in the 80s.

His marriage to actress Farrah Fawcett in the 70s, then at the height of her popularity as one of "Charlie's Angels", made them one of Hollywood's most watched couples until their 1981 divorce.