Changing magnitude, frequency, and timing of precipitation can influence aquatic-system hydrological, geochemical, and biological processes, in some cases resulting in system-wide shifts to an alternate state. Since the early 1990s, the southern Prairie Pothole Region has been subjected to an extended period of increased wetness resulting in marked changes to aquatic systems defining this region. We explored numerous lines of evidence to identify: (1) how the recent wet period compared to historical variability, (2) hydrological, geochemical, and biological responses, and (3) how these responses might represent a state shift in the region’s wetland ecosystems. We analyzed long-term climate records and compared how different hydrological variables responded in this wet period compared to decades before the observed shift. Additionally, we used multi-decadal records of waterfowl population and subsurface tile drain records to explore wildlife and human responses to a shifting climate. Since 1993, a novel precipitation regime corresponded with increased pond numbers, ponded-water depths, lake levels, stream flows, groundwater heights, soil-moisture, waterfowl populations, and installation of subsurface tile drains in agricultural fields. These observed changes reflect an alteration in water storage and movement across the landscape that in turn has altered solute sources and concentrations of prairie-pothole wetlands and has increased pond permanence. Combined, these changes represent significant evidence for a state shift in the ecohydrological functioning of the region’s wetland ecosystems, a shift that may require a significant refinement of the previously developed “wetland continuum” concept.