Until the 1930s, malaria was endemic throughout large swaths of the American South. We used a Poisson mixture model to analyze the decline of malaria at the county level in Alabama (an archetypical Deep South cotton state) during the 1930s. Employing a novel data set, we argue that, contrary to a leading theory, the decline of malaria in the American South was not caused by population movement away from malarial areas or the decline of Southern tenant farming. We elaborate and provide evidence for an alternate explanation that emphasizes the role of targeted New Deal-era public health interventions and the development of local-level public health infrastructure. We show that, rather than disappearing as a consequence of social change or economic improvements, malaria was eliminated in the Southern United States in the face of economic dislocation and widespread and deep-seated poverty.