In the late 1930s, Simon returned to France, dissatisfied with the development of her American film career and the backfiring of its related publicity. There, she appeared in the Jean Renoir film La Bête Humaine (The Human Beast) in 1938. With the outbreak of World War II, she returned to Hollywood and worked for RKO Radio Pictures where she achieved her greatest successes in English language cinema with The Devil and Daniel Webster (1941), Cat People (1942) and The Curse of the Cat People (1944); the latter two formed part of the horror film series produced by Val Lewton. These films did not lead to greater success and she languished in mediocre films until the end of the war.

After being spotted in a restaurant in June 1931, Simon was offered a film contract by Director Victor Tourjansky, which ended her plans to become a fashion designer. She made her screen debut in Le chanteur inconnu (The Unknown Singer, 1931), and quickly established herself as one of the country's most successful film actresses. Simon later told a reporter that she had no acting experience when making her first screen test for The Unknown Singer. In 1932, she was given more important roles and she rose to fame after starring in Marc Allégret's Lac aux dames (Ladies Lake, 1934), which was in her own opinion her first serious role since The Unknown Singer. In later interviews, Simon expressed her gratitude towards Allégret, feeling that he was responsible for her glory.

After seeing her in Ladies Lake, Darryl F. Zanuck brought her to Hollywood in August 1935 with a widespread publicity campaign. Before accepting an American contract, Simon completed two more films for Allégret, Les yeux noirs (Black Eyes, 1935) and Les beaux jours (1935). It was usual for foreign actresses to receive months of preparation before working, but Simon was given only a few weeks of English lessons before she was told to report on set. Meanwhile, the studio had trouble finding her a suitable role. She was scheduled to make her American film debut in A Message to Garcia (1936), playing a Spanish girl, but was replaced by Rita Hayworth. In mid-1935, she was cast in the female lead in Under Two Flags (1936), but was discharged during production.

Instead, the studio rushed her in the romantic comedy Ladies in Love (1936), which was filmed in mid-1936. She shared the female lead with Janet Gaynor, Loretta Young and Constance Bennett, some of whom objected to the large number of scenes that Simon was getting. It was a heavyweight lineup in which Simon's role left her little chance to compete effectively. Trying to avoid quarrels, she hired an assistant to prevent her from making headlines with her behavior. Despite a big build-up, which included a weekly salary even though her first American film was released more than a year after her arrival in the country, Simon's films for 20th Century Fox were only moderately successful. Among others, she was cast in the Janet Gaynor role in the 1937 remake of the silent classic Seventh Heaven (1927), which co-starred James Stewart and flopped. Afterwards, she was cast in Danger – Love at Work (1937), but due to her heavy French accent she had to be replaced by Ann Sothern. Failing in finding her appropriate roles, the studio allowed her to go on an eight-week vacation to France, and following her return in June 1937, she was assigned to Suez (1938), but the project was shelved and she was eventually replaced.

Simon never married. It was alleged by her secretary that she gave a gold key to her boudoir to any man she was interested in, including George Gershwin. However, as film Historian Greg Mank reports in his audio commentary for the DVD of Cat People the secretary was then on trial for extorting money from her employer, and her word on this matter cannot be taken at face value (the secretary was later convicted, and the terms of her probation required that she never speak of the "gold key" scandal again). In the 1950s, Simon was romantically involved with the French banker and racehorse owner/breeder Alec Weisweiller whose wife Francine was one of Jean Cocteau's patrons.

Simon died in Paris, France, on 22 February 2005, aged 94, from natural causes. The BBC mistakenly reported her age as 93 by using the wrong year of birth (1911). A few days later, French Minister of Culture Renaud Donnedieu de Vabres issued a statement in which he extolled Simon's "charm, her irresistible smile ... With Simone Simon's passing, we have lost one of the most seductive and most brilliant stars of the French cinema of the first half of the 20th century."

In 2011, British actor and Writer Stephen Mosley paid tribute to her in his acclaimed book of strange tales The Boy Who Loved Simone Simon.