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The Appalachian Mountains serve as a water source for important population centers in the eastern and midwestern United States. Despite this, the effects of climate change on the hydroclimatology of the region have not been thoroughly assessed, and its effects for water resources remain uncertain. In this study, we analyze the effects of climate change in a holistic approach to consider differential changes between atmospheric water supply (precipitation) and atmospheric water demand (potential evapotranspiration). We analyze the absolute and relative changes in both variables, as well as their relation (aridity index) and future projected shifts in their seasonality. Our findings show that precipitation is projected to increase in the northeastern part of the region and decrease in the southwest with a transition zone in the central Appalachians. Potential evapotranspiration increases consistently throughout the twenty-first century at a higher rate than precipitation, increasing the aridity of the region except for some small localized pockets at high elevations. The seasonality of precipitation indicates different shifts across the region related to changes in the dominant synoptic drivers of the region and changes in the seasonal characteristics of the land surface. All changes are exacerbated in the most extreme future climate scenario, highlighting the importance of local to global policies toward a more sustainable water resources development. In addition, we perform a basin-scale assessment on 20 major rivers with headwaters within the "Appalachian Region." Our basin-scale results enforce the gridded regional results and indicate that, as temperatures continue to increase, lowland areas will rely more heavily on higher-elevation forested headwater catchments for water supply.