His debut, The Benson Murder Case (1926), introduced Philo Vance, a stylish, erudite New York amateur detective whose deductions drew on psychology, art, and cultural knowledge. Vance became one of the most popular fictional detectives of the era, featured in twelve novels, including The Canary Murder Case (1927), The Greene Murder Case (1928), The Bishop Murder Case (1929)—widely regarded as his masterpiece—and The Garden Murder Case (1935). Many were adapted into successful Hollywood films.
Van Dine also authored the influential essay "Twenty Rules for Writing Detective Stories" (1928), which helped define the conventions of Golden Age detective fiction. Though his fame faded in the 1930s, he remains a foundational figure in American crime literature.