Climatic changes have altered surface water regimes worldwide, and climate projections suggest that such alterations will continue. To inform management decisions, climate projections must be paired with hydrologic models to develop quantitative estimates of watershed scale water regime changes. Such modeling approaches often involve downscaling climate model outputs, which are generally presented at coarse spatial scales. In this study, Coupled Model Intercomparison Project Phase 5 climate model projections were analyzed to determine models representing severe and conservative climate scenarios for the study watershed. Based on temperature and precipitation projections, output from GFDL-ESM2G (representative concentration pathway 2.6) and MIROC-ESM (representative concentration pathway 8.5) were selected to represent conservative (ΔC) and severe (ΔS) change scenarios, respectively. Climate data were used as forcing for the soil and water assessment tool to analyze the potential effects of climate change on hydrologic processes in a mixed-use watershed in central Missouri, USA. Results showed annual streamflow decreases ranging from −5.9% to −26.8% and evapotranspiration (ET) increases ranging from +7.2% to +19.4%. During the mid-21st century, sizeable decreases to summer streamflow were observed under both scenarios, along with large increases of fall, spring, and summer ET under ΔS. During the late 21st century period, large decreases of summer streamflow under both scenarios, and large increases to spring (ΔS), fall (ΔS) and summer (ΔC) ET were observed. This study demonstrated the sensitivity of a Midwestern watershed to future climatic changes utilizing projections from Coupled Model Intercomparison Project Phase 5 models and presented an approach that used multiple climate model outputs to characterize potential watershed scale climate impacts.