The impacts of climate change on surface water resources are relatively well studied, whereas groundwater resources have received much less attention globally. This study presents an analysis of climate change impacts on groundwater resources in a well-instrumented 6,800 km² watershed within the Laurentian Great Lakes Basin. We employ a physics-based modeling framework consisting of an ensemble of high-resolution regional climate projections from the Weather Research and Forecasting (WRF) model and the fully integrated three-dimensional hydrologic model HydroGeoSphere. The WRF model is run at resolutions as fine as 10 km with two different physics configurations, while HydroGeoSphere simulates the terrestrial hydrosphere at subkilometer scale, spanning from deep groundwater to surface water, including groundwater–surface water interactions. The two WRF physics configurations produce opposite climate change responses in summer precipitation. Hydrologic simulations generally follow the climate forcing; however, due to subsurface memory, summer differences propagate across the entire seasonal cycle. In the drier climate scenario, groundwater levels and recharge decline, whereas in the wetter scenario, groundwater levels rise (with recharge remaining largely unchanged). Soil moisture also responds, primarily during late summer. Importantly, the magnitude of climate change impacts on groundwater is strongly modulated by local physiographic conditions. Areas with a deep water table (>2 m; 15% of the basin) show particularly high sensitivity to changes in climate forcing. Moreover, changes in groundwater levels, recharge, and soil moisture tend to co-occur spatially, indicating the potential for compounding impacts.