After attending Northwestern University, Sheldon migrated to Hollywood, where he first worked at Universal at a reader earning $24 per week. His early credits include "Mr. District Attorney in the Carter Case" (1941), one of a series of Dennis O'Keefe programmers based on the radio show. With Frances Goodrich and Albert Hackett, Sheldon went on to co-author both the classic "Easter Parade" (1948), featuring Irving Berlin's music and lead turns by Fred Astaire and Judy Garland, and "Annie Get Your Gun" (1950), originally intended for Garland who was replaced by Betty Hutton. Subsequent films, however, were often minor. "Three Guys Named Mike" (1951) had Jane Wyman as a flight attendant trying to decide which beau to marry while "You're Never Too Young" (1955) was a twist on 1942's "The Major and the Minor", rewritten to accommodate the talents of Dean Martin and Jerry Lewis. Sheldon also directed and produced a few films, including "Dream Wife" (1953), in which Cary Grant married an Eastern Princess for good will reasons, and "The Buster Keaton Story" (1957), an unsuccessful rendition of the silent star's life starring Donald O'Connor.

While Sheldon worked steadily in feature films and was a respected screenwriter, he did not make the ranks of the prestigious legendary ones. His true fame and power base in Hollywood was yet to come. By the early 60s, Sheldon permanently drifted into TV. There had been a few earlier forays, such as the 1958 NBC special "Adventures of a Model", but it wasn't until he created "The Patty Duke Show" for ABC in 1963 that he had his first real hit. Even more successful was Sheldon's next venture, the longer-running "I Dream of Jeannie" (NBC, 1965-70), for which he contributed a number of scripts. He then created and executive produced "Nancy" (NBC, 1970-71), a short-lived sitcom about the daughter of a US president. In 1979, Sheldon created "Hart to Hart" for Aaron Spelling and ABC and co-wrote the two-hour pilot, a twist on "The Thin Man" formula. The successful series ran for several seasons and owed much to the chemistry of its stars, Robert Wagner and Stefanie Powers, although Sheldon's participation ceased after the initial outing. Both "Hart to Hart" and "I Dream of Jeannie" returned as TV-movie specials in the late 80s and 90s and "Jeannie" has been developed as a potential feature film as well.

Yet, this small screen success was not to be Sheldon's shining glory. Rather, it was his career as a novelist which would make him internationally famous. His popular fiction has been translated worldwide with hundreds of millions of copies in print. Into the 90s, Sheldon could boast of being one of the few novelists to have each book turned into either a feature film or TV miniseries. His first, "The Naked Face", was published in 1970 and this tale of a psychiatrist was filmed in 1985. The small screen, however, has been more hospitable to his work and adaptations include "Rage of Angels" (NBC, 1983), with Jaclyn Smith; the multi-generational "Master of the Game" (CBS, 1984), with Dyan Cannon; "If Tomorrow Comes" (CBS, 1986); and "Sidney Sheldon's 'Windmills of the Gods'" (CBS, 1988).

In the late 80s, Sheldon joined producer Michael Viner and actress Deborah Raffin in forming Dove Audio Books and Dove Productions. By 1991, through the latter company, Sheldon took control of his own productions, and with Viner turned out "Sidney Sheldon's 'Memories of Midnight'", a syndicated miniseries starring Jane Seymour, Omar Sharif and Stephen Macht. Raffin starred in "Sidney Sheldon's 'The Sands of Time'" (syndicated, 1992). Other longforms include his tale of dreamers in Hollywood, "A Stranger in the Mirror" (ABC, 1993) and "Sidney Sheldon's 'Nothing Lasts Forever'" (CBS, 1995), about three medical residents.