Rivers are essential to aquatic ecosystem and societal sustainability, but are increasingly impacted by water withdrawals, land-use change, and climate change. The relative and cumulative effects of these stressors on continental river flows are relatively unknown. In this study, we used an integrated water balance and flow routing model to evaluate the impacts of impervious cover and water withdrawal on river flow across the conterminous US at the 8-digit Hydrologic Unit Code (HUC) watershed scale. We then estimated the impacts of projected change in withdrawals, impervious cover, and climate under the B1 "Low" and A2 "High" emission scenarios on river flows by 2060. Our results suggest that compared to no impervious cover, 2010 levels of impervious cover increased river flows by 9.9% on average with larger impacts in and downstream of major metropolitan areas. In contrast, compared to no water withdrawals, 2005 withdrawals decreased river flows by 1.4% on average with larger impacts in heavily irrigated arid regions of Western US. By 2060, impacts of climate change were predicted to overwhelm the potential gain in river flow due to future changes in impervious cover and add to the potential reduction in river flows from withdrawals, decreasing mean annual river flows from 2010 levels by 16% on average. However, increases in impervious cover by 2060 may offset the impact of climate change during the growing season in some watersheds. Large water withdrawals will aggravate the predicted impact of climate change on river flows, particularly in the Western US. Predicted ecohydrological impacts of land cover, water withdrawal, and climate change will likely include alteration of the terrestrial water balance, stream channel habitat, riparian and aquatic community structure in snow-dominated basins, and fish and mussel extirpations in heavily impacted watersheds. These changes may also require new infrastructure to support increasing anthropogenic demand for water, relocation of agricultural production, and/or water conservation measures. Given that the impacts of land use, withdrawals and climate may be either additive or offsetting in different magnitudes, integrated and spatially explicit modeling and management approaches are necessary to effectively manage water resources for aquatic life and human use in the face of global change.