She was born Mary Elizabeth Hughes in Alton, Illinois. Hughes' parents, George Joseph Hughes and Mary Frances Hughes, separated when she was an infant and divorced in 1923. After the divorce, Hughes's mother moved with her only child to Washington, D.C. Hughes' grandmother, Flora Fosdick, was described as a "star of grand opera and drama [who] played with Ethel Barrymore on the stage."

As a child Hughes began acting in stage productions. While acting in a school play in the early 1930s, her performance caught the attention of Clifford Brown, a repertory theatre company owner, who offered her a part in a touring production of Alice in Wonderland. While touring with another production in Brown's company, she was offered a contract from a talent scout with Gaumont-British Studios but declined the offer to finish high school.

After graduating from high school in 1937 she returned to Brown's theatre company, where she continued to appear in various stage productions until the summer of 1938, when she relocated to Los Angeles with her mother to pursue a film career. After six months of failing to land movie roles, Hughes and her mother made plans to return to Washington, D.C., until Hughes met an agent, Wally Ross. Ross introduced Hughes to powerful william Morris agent Johnny Hyde. Hyde landed Hughes a contract with MGM, and she soon landed a small, uncredited role in the 1939 film Broadway Serenade.

In 1940, against Fox's wishes, Hughes began a relationship with actor Robert Stack. The romance lasted a year.

Her most famous role was as Henry Fonda's former girlfriend in the Best Picture Academy Award nominee, The Ox-Bow Incident (1943). Throughout the mid-40s and early '50s, Hughes appeared in film and television roles, including the cult classic I Accuse My Parents (which was later parodied on Mystery Science Theater 3000), Wanted: Dead or Alive (episode "Secret Ballot"), The Devil's Henchman, The Abbott and Costello Show, Dragnet and Studio One.

After her romance with Stack ended, Hughes married actor Ted North in 1943. The couple had one son, Donald, before divorcing in 1947. On April 28, 1948, she married singer/actor David Street. The marriage ended in divorce on January 23, 1956. In 1973 Hughes married her manager, Nicky Stewart, but that marriage also ended in divorce four years later.

In 1961, Hughes decided to retire from acting and began working as a receptionist in a plastic surgeon's office, although she continued her appearances in nightclubs. The following year she directed and starred in a Los Angeles production of Pajama Top. For the rest of the '60s she would go on to appear in television shows like Rawhide and Dennis the Menace. In 1970 she landed a regular role on The Red Skelton Show, appearing in 11 episodes before the show ended later that year. In 1976 she again retired from show Business, explaining that she was "tired of auditioning for sexy grandma roles." Hughes' last onscreen appearance was in the 1976 film Tanya.

In the late 1970s Hughes opened a beauty parlor in Canoga Park, California. She closed the shop in the late 1980s and began working as a telemarketer until 1991, when she was laid off.

Hughes died, aged 75, on August 27, 1995 from natural causes in Los Angeles.