She was brought to Hollywood by Warner Brothers for the film version of the latter. Jewell appeared in a variety of supporting roles during the early 1930s. She played stereotypical gangster's women in such films as Manhattan Melodrama (1934) and Marked Woman (1937). She was well received playing against type, as an innocent seamstress sentenced to death on the guillotine, in A Tale of Two Cities (1935).
Her most significant role was as the prostitute Gloria Stone in Lost Horizon (1937). In the mid to late 1930s, Jewell was seen at nightclubs withWilliam Hopper (who appeared on Perry Mason and was the son of gossip columnist Hedda Hopper and stage star DeWolf Hopper).
Jewell's films included Gone with the Wind (1939) (in the role of "that white trash, Emmy Slattery"), Northwest Passage (1940), High Sierra (1941), and the low-budget The Leopard Man (19 43). By the end of the 1940s, her roles had reduced in significance to the degree that her performances were often uncredited, e.g. The Snake Pit. She also performed in radio dramas in the 1950s, including This is Your FBI.
In 1972, she appeared opposite Edie Sedgwick in the film Ciao! Manhattan. Her final film was the B movie Sweet Kill (1973), the directorial debut of future Academy Award winner Curtis Hanson.
Jewell died in Los Angeles, California, aged 64, from undisclosed causes.
Isabel Jewell was recognized with a star on the Hollywood Walk of Fame for her contribution to motion pictures.