Domergue appeared in science-fiction and horror pictures, such as Cult of the Cobra, This Island Earth, It Came from Beneath the Sea, and The Atomic Man, all released in 1955, earning her a reputation as an early "scream queen".

While a sophomore at University High School, she signed a contract with Warner Bros.,[11] and made her first on-screen appearance with an uncredited walk-on role in Blues in the Night (1941).

[13] After graduating in 1942, Domergue continued to pursue a career in acting, but after sustaining injuries in a near-fatal car accident, her plans were put on hold.

The film had a long and troubled production history, with reshoots and several changes of director, further exacerbated by Hughes's health problems following a near-fatal plane crash he endured in July 1946.

The New York Times panned the film as "a garrulous, slow, and obvious period piece, weighed down by a profusion of exotic accents, undistinguished dialogue, and unconvincing play acting... set against a background of the wild, Corsican countryside, which does give the picture an atmosphere of suspenseful authenticity".

[18] Following Vendetta, Domergue freelanced in the film noir Where Danger Lives (1950), playing a femme fatale opposite Robert Mitchum and Claude Rains.

Bosley Crowther, in The New York Times, criticized Domergue's performance for "manifest[ing] nothing more than a comparatively sultry appearance and an ability to recite simple lines".

[20] Her final credit for RKO was the drama This Is My Love (1954), which was shot after the release of her first film with Universal, The Duel at Silver Creek (1952), in which she appeared opposite Audie Murphy.

[21] In 1955, Domergue appeared in another Western, Santa Fe Passage, playing an ammunition retailer opposite John Payne and George Keymas.

[23] This was followed with a role in Columbia Pictures's It Came from Beneath the Sea (1955), a science-fiction, monster film that was a major commercial success, grossing $1.7 million at the box office.

In the late 1960s, she appeared in several Italian giallo films, including Lucio Fulci's One on Top of the Other (1969), and Alberto De Martino's The Man with Icy Eyes (1971).