Streamflow is an important source of water for industrial and domestic uses. Changes in the trends and intra-annual variations of streamflow pose a challenge to water resources management. However, our current understanding of the relative importance of the drivers of streamflow changes is not comprehensive. The goal of this research is to examine the dominant drivers of changes in streamflow over space and time and predict future streamflow across the contiguous United States. To achieve this goal, four objectives are accomplished: (1) identify the time-varying dominant drivers of streamflow change as a function of climate and land-use characteristics from 1950 to 2009, (2) investigate spatial heterogeneity of the controls of surface water balance by considering anthropogenic factors, (3) predict future changes in streamflow under climate and land-use change from 2040 to 2069, and (4) identify the dominant hydrological drivers at a seasonal timescale. The hydrological drivers are precipitation, potential evapotranspiration, and other factors represented by the Budyko ω parameter (e.g., climate seasonality, agricultural drainage, and urbanization).