Society and the environment in the arid southwestern United States depend on reliable water availability, yet current water use outpaces supply. Water demand is projected to grow in the future and climate change is expected to reduce supply. To adapt, water managers need robust estimates of future regional water supply to support management decisions. To address this need, we estimate future streamflow in seven water resource regions in the southwestern U.S. using a new SPAtially Referenced Regressions On Watershed attributes (SPARROW) streamflow model. We present streamflow projections corresponding to input data from seven climate models and two greenhouse gas Representative Concentration Pathways (RCP4.5 and 8.5) for three, thirty-year intervals centered on the 2030s, 2050s, and 2080s, and for a historical thirty year interval centered on the 1990s. Across water resource regions, about half of the RCP4.5 models (51%) and two thirds of the RCP8.5 models (67%) indicate decreases in streamflow in the 2080s relative to the historical period. Models project maximum decreases in streamflow of 36–80% in all water resource regions for all periods and RCPs relative to historical streamflow, and maximum streamflow decreases of up to 20–45% in the 2080s at sites along the Colorado River used for measuring compliance with interstate and international water agreements. Headwaters are projected to experience the greatest declines, with substantial downstream implications. Among these estimates, the streamflows from models forced with RCP8.5 tend to be lower than those forced with RCP4.5. Not all climate models, times, and RCPs project widespread streamflow declines. The most ubiquitous streamflow increases are projected to occur in the 2030s under RCP4.5. Later time periods and enhanced greenhouse gas forcings indicate smaller regions of streamflow increase and lower accumulated streamflows, suggesting that limiting or reducing greenhouse gas concentrations could support future water availability. Although some possible streamflow increases are promising, the modest and spatially limited increases in streamflow projected for later time periods are still unlikely to be sufficient to meet the projected water demand. These results inform the likelihood of future water agreement compliance, and support developing strategies to balance water supply and demand.