Predicting how precipitation becomes runoff is essential for managing floods, droughts, water quality, and climate adaptation. In North America’s Prairie Pothole Region, one of the world’s largest wetland complexes and a key agricultural zone, we show that year-to-year runoff is governed not just by climate, but by dynamic wetland inundation. Many catchments exhibit threshold-like behavior, where streamflow surges only after wetlands exceed critical inundation levels. Our findings highlight the vital buffering role of geographically isolated wetlands, which are often unprotected despite regulating the timing and magnitude of water, nutrient, and carbon fluxes. This work challenges climate-centric runoff models and offers timely insights for wetland conservation, flood forecasting, and adaptive water policy across both the U.S. and Canadian Prairie landscapes.