Wetland productivity in the Prairie Pothole Region (PPR) of North America is closely linked to climate. A warmer and drier climate, as predicted, will negatively affect the productivity of PPR wetlands and the services they provide. The effect of climate change on wetland productivity, however, will not only depend on natural processes (e.g., evapotranspiration), but also on human responses. Agricultural land use, the predominant use in the PPR, is unlikely to remain static as climate change affects crop yields and prices. Land use in uplands surrounding wetlands will further affect wetland water budgets and hence wetland productivity. The net impact of climate change on wetland productivity will therefore depend on both the direct effects of climate change on wetlands and the indirect effects on upland land use. We examine the effect of climate change and land-use response on semipermanent wetland productivity by combining an economic model of agricultural land-use change with an ecological model of wetland dynamics. Our results suggest that the climate change scenarios evaluated are likely to have profound effects on land use in the North and South Dakota PPR, with wheat displacing other crops and pasture. The combined pressure of land-use and climate change significantly reduces wetland productivity. In a climate scenario with a +4 °C increase in temperature, our model predicts that almost the entire region may lack the wetland productivity necessary to support wetland-dependent species.