Gifford was born and raised in Long Beach, California and at the age of 16 had applied to UCLA School of Law with no intention of pursuing an acting career. With a friend, she visited the studios of Samuel Goldwyn to watch a film being made and while there was spotted by a talent scout who brought her to the attention of Goldwyn, who signed her to an acting contract.
After only receiving minor roles, Gifford moved to RKO where she was cast in several uncredited supporting roles in films of the late 1930s, including Stage Door (1937) starring Katharine Hepburn and Ginger Rogers.
In 1938, at the age of 18, Gifford married character actor James Dunn and in 1939 landed her first leading role, in the low-budget Mercy Plane, opposite her husband. A planned retirement was interrupted briefly when she played another uncredited role in James Stewart's break-out film Mr. Smith Goes to Washington (1939).
Gifford played several more minor roles before she was, in 1941, loaned to Republic Pictures and cast in the role which would arguably produce her most enduring fame: as the semi-clad Nyoka in Jungle Girl, a 15-chapter movie serial, based very loosely on the novel by Edgar Rice Burroughs. The role was the first time since Pearl White in the silent era that an actress had played the lead in the movie serial genre.
The following year, Republic made a sequel Perils of Nyoka but Gifford was no longer available and the heroine's part was played by Kay Aldridge. In the Walt Disney feature, The Reluctant Dragon (film) (1941) as Doris, a studio artist, Gifford had a leading role.
With Gifford's film career gaining momentum and Dunn's on the decline, partly due to his battle with alcoholism, the marriage had failed by 1942. She left RKO for Paramount Pictures where she acted in several films including The Glass Key (1942). In 1943 she made another jungle movie, co-starring with Johnny Weissmuller in Tarzan Triumphs at RKO. That year she also left Paramount and moved to the prestigious Metro-Goldwyn-Mayer studio with the sponsorship of an MGM executive.
At MGM there was more success playing leading roles in such films as Our Vines Have Tender Grapes (1945) and She Went to the Races (1945) and the more notable The Arnelo Affair (1947). Gifford also played in supporting roles including Thrill of a Romance (1945) with Esther Williams, and Luxury Liner (1948) with Jane Powell.
In 1948, Gifford was almost killed in a car accident, an event that sidelined her career and caused a decline in her health. She received severe head injuries, resulting in a drastic change in her personality. She began to lose confidence in her abilities and found it difficult to come back to films. Losing her contract with MGM, she attempted a comback in two early 1950s B films, Riding High (1950) and Sky Commando (1953). During the 1950s, her mental and physical health declined to the point where she was placed into Camarillo State Mental Hospital in 1958. She would spend almost the entire next 25 years in and out of various institutions.
In 1983, Richard S. Fisher, a journalist for a film magazine, traced down Gifford who had lately been volunteering at the Pasadena, California City Library, having apparently recovered. She spent her final years in quiet obscurity and died of emphysema in a convalescent center in Pasadena at the age of 73. Despite reports that she is the sister of football star Frank Gifford (also from southern California), the latter clearly indicates in his autobiography that his "clan" consisted of a brother Waine and a sister Winona. Frances, evidently, was no relation.