Numerous wetlands in North America’s Prairie Pothole Region (PPR) provide important ecosystem services to surrounding areas, yet are threatened by climate and land-use changes. Understanding the impacts of climate change on prairie wetlands is critical to effective conservation planning. In this paper, we construct a wetland model with surface water balance (soil water content) and ecoregions and apply it to predict future wetland distribution under a climate change scenario. The future climate forcing is from a dynamical downscaling approach of a high-resolution convection-permitting regional climate model. The results show that the impacts of climate change on wetland extent are spatially heterogeneous and seasonally varied. The future wetter climate in the western PPR will favor increased wetland abundance in both spring and summer. In the eastern PPR, particularly in the moist mixed grassland and aspen parkland, the wetland area will increase in spring but experience enhanced declines in the summer due to strong evapotranspiration. When combined with historical patterns of anthropogenic drainage, results suggest that diverse conservation and restoration strategies will be needed. The outcomes of this study will be useful to conservation agencies to ensure that current investments will continue to provide good conservation returns in the future.