Cholera remains a major public health threat in many developing countries around the world. The striking seasonality and annual recurrence of this infectious disease in endemic areas remain of considerable interest to scientists and public health workers. Despite major advances in the ecological and microbiological understanding of Vibrio cholerae, the causative agent of the disease, the role of underlying large-scale hydroclimatic processes in propagating the disease for different seasons and spatial locations is not well understood. Here we show that the cholera outbreaks in the Bengal Delta region are propagated from the coastal to the inland areas and from spring to fall by two distinctly different transmission cycles, premonsoon and postmonsoon, influenced by coastal and terrestrial hydroclimatic processes, respectively. A coupled analysis of the regional hydroclimate and cholera incidence reveals a strong association of the space-time variability of incidence peaks with seasonal processes and extreme climatic events. We explain how the asymmetric seasonal hydroclimatology affects regional cholera dynamics by providing a coastal growth environment for bacteria in spring, while propagating the disease to fall by monsoon flooding. Our findings may serve as the basis for “climate-informed” early warnings and for prompting effective means for intervention and preempting epidemic cholera outbreaks in vulnerable regions.