Coinciding with his rise to fame on Kildare, Chamberlain also had a brief but moderately successful career as a pop singer. Chamberlain subsequently became disenchanted with Hollywood and turned to the theater, finding success in England among British audiences.

During the first half of the 1970s Chamberlain enjoyed some success in films with The Towering Inferno, The Last Wave, "The Three Musketeers" and sequels and The Count of Monte Cristo though was never regarded as an out-and-out leading man. In The Slipper and the Rose, a musical version of the Cinderella story, co-starring Gemma Craven, he displayed his vocal talents, which had already resulted in a hit single during his days as Dr. Kildare.

Chamberlain later appeared in several popular miniseries, including Centennial, The Man in the Iron Mask, Shogun, and The Thorn Birds. In the late 1980s he experienced a belated breakthrough as a leading man with King Solomon's Mines, and also played Jason Bourne in the original 1988 version of The Bourne Identity.

He eventually "retired" to Hawaii where he owns land with his partner, agent, producer, and director, Martin Rabbett, but he never stopped working. Since the 1990s Chamberlain has mostly appeared in television movies and as a guest star on series including The Drew Carey Show and Will & Grace.

Although it was generally known that Chamberlain was gay, having been outed by the French women's magazine Nous Deux in December 1989, it was not until 2003, at age 69, that he came out as such in his biography entitled Shattered Love (ISBN 0060087439), which describes how he felt obliged to hide his sexuality in order to have an acting career. He evidently ceased having any such inhibitions when he appeared in very high drag as Nigel Wick (played by Craig Ferguson)'s (British) mother on The Drew Carey Show.

Chamberlain's father, the late Charles Chamberlain ("Chuck C.") was a well known circuit speaker in Alcoholics Anonymous; he died in 1984.