The Prairie Pothole Region (PPR) of Canada contains millions of small isolated wetlands and is unique to North America. The goods and services of these isolated wetlands are highly sensitive to variations in precipitation and temperature. We evaluated the flood proofing of isolated wetlands (pothole wetlands) under various climate change scenarios in the Upper Assiniboine River Basin (UARB) at Kamsack, a headwater catchment of the Lake of the Prairies in the Canadian portion of the PPR. A modified version of the Soil Water Assessment Tool (SWAT) model was utilized to simulate projected streamflow under the potential impacts of climate change, along with changes to the distribution of pothole wetlands. Significant increases in winter streamflow (~200%) and decreases (~11%) in summer flow, driven by changes in future climates, were simulated. Simulated changes in streamflow resulting from pothole removal were between 55% for winter and 15% for summer, suggesting that climate will be the primary driver in the future hydrologic regime of the study region. This research serves as an important guide to the various stakeholder organizations involved in quantifying the aggregate impacts of pothole wetlands in the hydrology of the Canadian Prairie Region.