Born in Crouch Hill, London, England, Simmons began acting at the age of 14. Prior to moving to Hollywood, she distinguished herself in such roles as the young Estella in David Lean's Great Expectations (1946) and Ophelia in Olivier's opus Hamlet in 1948. By this time, she was already well known for her work in other British films and her stage career.

In 1950, she married the English actor Stewart Granger, with whom she appeared in several films, successfully making the transition to Hollywood. Among her best-known leading roles are The Robe (1953) The Egyptian (1954), Guys and Dolls (1955), The Big Country (1958), Elmer Gantry (1960) (directed by her second husband, Richard Brooks), Spartacus (1960), and The Happy Ending, again directed by Brooks and for which she received her second Oscar nomination.

By the 1970s, Simmons turned her focus to stage and television acting. She toured the United States in the well-reviewed A Little Night Music, then took the show to London. For her appearance in the mini-series The Thorn Birds, she won an Emmy Award.

In 1988, she starred in her first film for 10 years, titled The Dawning with Anthony Hopkins and Hugh Grant, and in 1989 she again starred in a miniseries version of Great Expectations, where she performed the role of Miss Havisham, Estella's adoptive mother, as well as in 1985 and 1986 in North & South.

Simmons made a late career appearance in the Star Trek: The Next Generation episode "The Drumhead" as a witch-hunt inspiring investigator named Admiral Nora Satie.