She is also a great-grandniece of Giovanni Schiaparelli, an Italian Astronomer who was the first to describe the so-called canals of Mars, and a second cousin, once removed, of art expert Bernard Berenson (1865–1959) and his sister Senda Berenson (1868–1954), an athlete and educator who was one of the first two women elected to the Basketball Hall of Fame.

In the early 1970s, Berenson was the companion of the French banking heir Baron David René de Rothschild, the younger son of Baron Guy de Rothschild. She was also in a relationship with Austrian actor Helmut Berger.

Eventually, she was cast in several prominent film roles, including Gustav von Aschenbach's wife in Luchino Visconti's 1971 film Death in Venice, the Jewish department store heiress Natalia Landauer in the 1972 film Cabaret, for which she received acclaim (including two Golden Globe nominations, a BAFTA nomination and an award from the National Board of Review), and the tragic beauty Lady Lyndon in the Stanley Kubrick film Barry Lyndon (1975). Vincent Canby of The New York Times stated of her performance: "Marisa Berenson splendidly suits her costumes and wigs." She recalled her experience working under Kubrick's direction:

A fashion model who came to prominence in the 1960s—"I once was one of the highest paid Models in the world", she told The New York Times—Berenson appeared on the cover of the July 1970 issue of Vogue as well as the cover of Time on December 15, 1975. She appeared in numerous fashion layouts in Vogue in the early 1970s and her sister Berry was a Photographer for the magazine as well. She was known as "The Queen of the Scene" for her frequent appearances at nightclubs and other social venues in her youth, and Yves Saint Laurent dubbed her "the girl of the Seventies".

Her first husband was James Randall, a rivet manufacturer; they wed in Beverly Hills, in 1976 and divorced in 1978. The couple have one daughter, Starlite Melody Randall (born 1977).

Berenson appeared in a number of other movies including Casanova & Co. (1977), Killer Fish (1979), the Blake Edwards comedy S.O.B. (1981), The Secret Diary of Sigmund Freud (1984) and Clint Eastwood's White Hunter Black Heart (1990), as well as in made-for-TV movies in the United States, such as the Holocaust-themed drama Playing for Time (1980). She guest-hosted an episode of The Muppet Show during its third season in 1978. She made her Broadway debut in the 2001 revival of Design for Living, which also starred Jennifer Ehle, Alan Cumming and Dominic West. In 2009, she appeared in the film I Am Love.

Her second husband was Aaron Richard Golub, a Lawyer, whom she married in 1982 and divorced in 1987. During the divorce proceedings, the judge ruled "the increased value of Ms. Berenson's acting and modeling career during the marriage were marital property" and therefore subject to consideration in any settlement agreements.

On September 11, 2001, her younger sister and sole sibling, Berry Perkins, widow of actor Anthony Perkins, was killed in the first FLIGHT to hit the World Trade Center. Marisa was also in an airplane during the terrorist attacks, flying from Paris to New York. In an interview with CBS, she told of the experience and how hours later she landed in Newfoundland (flights were diverted to Canada), and was told of her sister's death by a phone call with her daughter. Said Berenson: "I have hope and tremendous faith. I think that's what gets you through life ... through tragedies is when you have faith."

In August 2016 she appeared in a production of Romeo and Juliet in London, as Lady Capulet.