Despite the importance of surface water to people and ecosystems, few studies have explored detectable changes in surface water supply in a changing climate, given its large natural variability. Here we analyze runoff projections from the Variable Infiltration Capacity hydrological model driven by 97 downscaled and bias-corrected Coupled Model Intercomparison Project Phase 5 climate projections over the conterminous United States (CONUS). Our results show that more than 40% of the CONUS land area will experience significant changes in the probability distribution functions (i.e. PDFs) of summer and winter runoff by the end of the 21st century, which may pose great challenges to future surface water supply. Sub-basin mean runoff PDFs are projected to change significantly after 2040s depending on the emission scenarios, with earliest occurrence in the Pacific Northwest and northern California regions. When examining the response as a function of changes in the global mean temperature (ΔGMT), a linear relationship is revealed at the 95% confidence level. Generally, 1 °C increase of GMT leads to 11% and 17% more lands experiencing changes in summer and winter runoff PDFs, respectively. Such changes in land fraction scale with ΔGMT at the country scale independent of emission scenarios, but the same relationship does not necessarily hold at sub-basin scales, due to the larger role of atmospheric circulation changes and their uncertainties on regional precipitation. Further analyses show that the emergence of significant changes in sub-basin runoff PDFs is indicative of the emergence of new hydrology regimes and it is dominated by the changes in variability rather than shift in the mean, regardless of the emission scenarios.