This study examines the relative roles of climatic variables in altering annual runoff in the conterminous United States (CONUS) in the 21st century, using a monthly ecohydrological model (the Water Supply Stress Index model, WaSSI) driven with historical records and future scenarios constructed from 20 Coupled Model Intercomparison Project Phase 5 (CMIP5) climate models. The results suggest that precipitation has been the primary control of runoff variation during the latest decades, but the role of temperature will outweigh that of precipitation in most regions if future climate change follows the projections of climate models instead of the historical tendencies. Besides these two key factors, increasing air humidity is projected to partially offset the additional evaporative demand caused by warming and consequently enhance runoff. Overall, the projections from 20 climate models suggest a high degree of consistency on the increasing trends in temperature, precipitation, and humidity, which will be the major climatic driving factors accounting for 43–50, 20–24, and 16–23 % of the runoff change, respectively. Spatially, while temperature rise is recognized as the largest contributor that suppresses runoff in most areas, precipitation is expected to be the dominant factor driving runoff to increase across the Pacific coast and the southwest. The combined effects of increasing humidity and precipitation may also surpass the detrimental effects of warming and result in a hydrologically wetter future in the east. However, severe runoff depletion is more likely to occur in the central CONUS as temperature effect prevails.