Moore was born in Roswell, New Mexico, but spent much of her childhood and teenage years in the suburbs of Pittsburgh. As a child, she had a difficult and unstable home life. Her biological father, Charles Harmon, left her mother, Virginia, after a two-month marriage, before Moore was born. As a result, Moore had the surname of her stepfather, Danny Guynes, on her birth certificate. Danny Guynes, who committed suicide in 1980, frequently changed jobs and made the family move a total of forty times. Moore's parents were also alcoholics and often fought and beat each other. To make matters worse, operations on Moore's left eye during childhood required her to wear an eyepatch.

Moore's family settled in Los Angeles in 1976. When Moore was sixteen, her then-friend, actress Nastassja Kinski, persuaded her to drop out of Hollywood's Fairfax High School to become an actress. After quitting school, Moore went to work as a pin-up girl, modelled in Europe, and worked at a collection agency. Her half-brother, Michael Moore, once had a crush on her before it was determined they were related. He is famous for his documentary Fahrenheit 9/11.

In the early 1980s, Moore posed for a series of soft-core photographs featuring full frontal nudity. These photos went unnoticed until after she became a star, and were eventually published in a German magazine and later in North America. Moore's film debut was in the 1982 3-D science fiction/horror film, Parasite, which was a hit on the drive-in circuit, ultimately grossing $6 million. However, Moore was not widely known until she played the part of Jackie Templeton on the ABC soap opera, General Hospital, from 1982 to 1983.

In the 1980s, she appeared in several youth-oriented films, and was mentioned as being a member of the "Brat Pack".

For a time during the 1990s, Moore was the highest-paid actress in Hollywood. She had a string of box-office successes, including Ghost, A Few Good Men, and Indecent Proposal, and was the first actress to reach the $10 million salary mark. Among other films for which Moore was considered were Basic Instinct, Batman & Robin, Flashdance, Runaway Bride, and While You Were Sleeping. Moore's reputation suffered when the starring vehicles The Scarlet Letter, The Juror, Striptease, and G.I. Jane (a movie in which Moore shaved off all her long hair on camera, leaving her head totally bald) failed at the box office and garnered mixed reviews.

In August 1991, Moore appeared nude on the cover of Vanity Fair magazine while seven months pregnant with her daughter Scout LaRue, with enormous attendant publicity. The image was endlessly parodied (including by Spy magazine, which placed her then-husband Bruce Willis's head on her body), but also spawned honest imitators as other pregnant celebrities posed nude. Moore again appeared on the cover of Vanity Fair in August 1992, wearing only a body painted "suit".

After a break from her acting career, Moore returned to the screen as a former member of Charlie's Angels in the 2003 film Charlie's Angels 2: Full Throttle.

In August 1979, Moore began dating rock musician/songwriter Freddy Moore, whose last name she adopted; the two married in February 1980. The relationship lasted only 6 years (August 1979-August 1985). Moore began dating actor Emilio Estevez and began divorce procedings in 1985, and the two were engaged until 1987. She also dated actor John Stamos during the time when the two worked together on General Hospital.

On November 21, 1987, Moore married actor Bruce Willis, after a highly publicized whirlwind romance (the two met in August of that year). The couple has three daughters, Rumer Glenn (born August 16, 1988), Scout LaRue (born July 20, 1991), and Tallulah Belle (born February 3, 1994). Willis and Moore announced their separation in June of 1998, and divorced in 2000.

Moore also became a staple of tabloids due to her romantic relationship with actor Ashton Kutcher, who is sixteen years her junior. Both would eventually spoof the public's fascination with their age difference during a monologue on the March 19, 2005 episode of Saturday Night Live. Kutcher, who served as guest host, brought Moore on stage while Moore was made up to appear like an old woman who constantly babied Kutcher. Moore and Kutcher were married on Saturday, September 24, 2005 in a lavish, private ceremony conducted by a Kabbalah Centre rabbi and attended by about 100 close friends and family (Bruce Willis included).