Characterization of shifts in regional hydroclimatic conditions helps reduce negative consequences on agriculture, environment, economy, society, and ecosystem. This study assesses shifts in regional hydroclimatic conditions across the conterminous United States in response to climate change over the 21st century. The hydrological responses of five downscaled climate models from the Multivariate Adaptive Constructed Analogs data set ranging from the driest to wettest and least warm to hottest were simulated using the variable infiltration capacity (VIC) model. Shifts in regional hydroclimatic conditions at 8-digit hydrologic unit scale (HUC8) were evaluated by the magnitude and direction of movements in the Budyko space. HUC8 river basins were then clustered into seven unique hydroclimatic behavior groups using the K-means method. A tree classification method was proposed to illustrate the relationships between hydroclimatic behavior groups and regional characteristics. The results indicate that hydroclimatic responses may vary from a river basin to another, but basins in the same neighborhood follow a similar movement in the Budyko space. The systematic hydroclimatic behavior of river basins is highly associated with their regional landform, climate, and ecosystem characteristics. Most HUC8s with mountain, plateau, and basin landform types will likely experience less arid conditions. However, most HUC8s with Plain landform type behave differently according to the regional ecosystem and climate. This study provides a potential roadmap of shifts in regional hydroclimatic conditions of U.S. river basins, which can be used to improve regional preparedness and ability of various sectors to mitigate or adapt to the impacts of future hydroclimate change. Plain Language Summary Long-term changes in climate and water availability may lead to aridification or desertification of river basins. This study characterizes regional changes in the relationship between climate and water budgets of river basins across the continental United States over the 21st century. Results provide insights for decision-makers and water planners to prepare for changes in factors that influence the vulnerability to water shortage. In the CONUS, hydroclimatic parameters such as precipitation, temperature, evaporation, water yield (or total runoff), and potential evapotranspiration have been projected to change over the 21st century (Hay et al.