Climate change poses major challenges for conservation and management because it alters the area, quality, and spatial distribution of habitat for natural populations. To assess species’ vulnerability to climate change and target ongoing conservation investments, researchers and managers often consider the effects of projected changes in climate and land use on future habitat availability and quality and the uncertainty associated with these projections. Here, we draw on tools from hydrology and climate science to project the impact of climate change on the density of wetlands in the Prairie Pothole Region of the USA, a critical area for breeding waterfowl and other wetland-dependent species. We evaluate the potential for a trade-off in the value of conservation investments under current and future climatic conditions and consider the joint effects of climate and land use. We use an integrated set of hydrological and climatological projections that provide physically based measures of water balance under historical and projected future climatic conditions. In addition, we use historical projections derived from ten general circulation models (GCMs) as a baseline from which to assess climate change impacts, rather than historical climate data. This method isolates the impact of greenhouse gas emissions and ensures that modeling errors are incorporated into the baseline rather than attributed to climate change. Our work shows that, on average, densities of wetlands (here defined as wetland basins holding water) are projected to decline across the U.S. Prairie Pothole Region, but that GCMs differ in both the magnitude and the direction of projected impacts. However, we found little evidence for a shift in the locations expected to provide the highest wetland densities under current vs. projected climatic conditions. This result was robust to the inclusion of projected changes in land use under climate change. We suggest that targeting conservation towards wetland complexes containing both small and relatively large wetland basins, which is an ongoing conservation strategy, may also act to hedge against uncertainty in the effects of climate change.