Halperin began his career as a filmmaker in 1922, working as a writer on The Danger Point (an original story). In two years he was working as a writer-producer-director on the Agnes Ayres film, When a Girl Loves. He is best known for his 1932 horror film White Zombie, starring Madge Bellamy and Bela Lugosi. Once thought "lost", the film has grown in stature over the years, first gaining a cult status, and eventually becoming recognized as one of the leading classics of the genre. Years after the film's release, Victor Halperin expressed a distaste for his horror films: "I don't believe in fear, violence, and horror, so why traffic in them?"
Halperin often worked in collaboration with his brother Edward. The Halperin Brothers produced a series of independent low-budget films in the 1930s. Victor Halperin retired in 1942, after working as a director at PRC studios.