Moving to Hollywood the following year and eliminating all but slight traces of her British accent, Lupino appeared for the rest of the decade in a series of modest ingenue roles, several of which ("Peter Ibbetson" 1935, "Anything Goes" 1936) gave her at least a slight chance to sparkle. It was not until 1939, though, that she really attracted critical attention as Ronald Colman's tormented Cockney painter's model in "The Light That Failed", a showy supporting role Lupino snagged after vigorously campaigning for the role and auditioning for director William Wellman. Dusky-voiced and dark-haired, with large eyes and a small, slightly angular face, Lupino came into her own playing headstrong, grasping women in a string of Warner Bros. melodramas through the 1940s. Especially memorable roles include a scheming waitress who cracks up in court on the witness stand in "They Drive By Night" (1940); John Garfield's and Humphrey Bogart's romantic interest in, respectively, "The Sea Wolf" and "High Sierra" (both 1941); the austere housekeeper turned murderess in "Ladies in Retirement" (1941, her favorite role); the ambitious "stage-sister" determined to make her sibling a star in "The Hard Way" (1943); the world-weary nightclub singer in the wonderful sudser "The Man I Love" (1946); and the shy, stuttering woman who shelters an escaped convict in the touching "Deep Valley" (1947).
Combining the nervous energy and, to a lesser extent, the clipped speech patterns of Bette Davis with a toughness characteristic of Barbara Stanwyck, Lupino managed to score an impressive lineup of characterizations at Warners despite the fact that she, Ann Sheridan and other stars were often left to dicker for the roles Davis turned down. Free-lancing after 1947, she continued to shine in melodramas including such worthy entries as "Lust for Gold" (1949), "On Dangerous Ground" (1952), "The Big Knife" (1955) and "While the City Sleeps" (1956). The restless actress began to tire of performing in the same types of melodrama she had done for years, though, and, caring more about "develop(ing) talent in others ... than in my own", Lupino formed a series of production companies and began developing projects. After managing to get several modest films off the ground as producer, she took to directing one herself, the skillfully told story of an unwed mother, "Not Wanted" (1949), when credited director Elmer Clifton had a heart attack after three days shooting. She made her credited directorial debut soon after with "Never Fear" (1949), a semi-documentary styled look at a dancer stricken with polio, an affliction Lupino herself had known as a child.
One of the few women directors to succeed in a male-dominated field, Lupino's seven low-budget feature films have generally attracted less critical attention than fellow director Dorothy Arzner's dozen-plus, partly because Lupino's work, often showing the victimization of women, seemed to some to be "feminist films made from an unfeminist viewpoint". More recent critics dissent, however, finding in her oeuvre compelling portraits of both victims and aggressors wandering through artfully delineated back-street milieus of postwar America. Although perhaps none of her features is an unsung masterpiece, her work is technically very competent (her editing skills being especially notable) and, long before the advent of the TV-movie, dealt with timely, controversial social issues in an intimate, measured manner. Her work includes such films as "Outrage" (1950), an early study of the effects of rape on a young woman, "Hard, Fast and Beautiful" (1951), an entertaining melodrama about an ambitious stage mother in the world of professional tennis, "The Hitchhiker" (1953), a gripping suspense noir, and "The Bigamist" (1953), a deftly handled melodrama which avoids placing the blame too simply on either a man or his two wives.
Reputed to be the young medium's first female helmer, Lupino did most of her subsequent directing for TV, much of it featuring a brand of skillful camerawork that typed her in action drama rather than in the drawing room. She turned out over 100 episodes of such series as "The Untouchables", "The Twilight Zone", "Have Gun, Will Travel", "The Fugitive" and her own show, "Mr. Adams and Eve". During the 60s and 70s, she made occasional TV and feature film acting appearances in "guest star" types of roles. On TV Lupino was the villainous Dr. Cassandra on "Batman". Most notably she was Steve McQueen's oddly youthful mother in Sam Peckinpah's gentle, low-key "Junior Bonner" (1972). Lupino's final acting job was a guest shot on "Charlie's Angels". She was married to actor Louis Hayward (1938-45), executive Collier Young (1948-50), who executive produced "Mr. Adams and Eve" in the late 50s, and actor Howard Duff (1951-73), her co-star in "Mr. Adams and Eve".