The ability to predict spatial variation in streamflow at the watershed scale is essential to understanding the potential impacts of projected climate change on aquatic systems in this century. However, problems associated with single outlet-based model calibration and validation procedures can confound the prediction of spatial variation in streamflow under future climate change scenarios. The goal of this study is to calibrate and validate a distributed hydrologic model, the Soil and Water Assessment Tool (SWAT), using distributed streamflow data (1978–2009), and to assess the potential impacts of climate change on future streamflow (2051–2060 and 2086–2095) for the Rock River (RRW), Illinois River (IRW), Kaskaskia River (KRW), and Wabash River (WRW) watersheds in the Midwestern United States, primarily in Illinois. The potential impacts of climate change on future water resources are assessed using SWAT streamflow simulations driven by projections from nine global climate models (GCMs) under a maximum of three SRES scenarios (A1B, A2, and B1). Results from model validation indicate reasonable spatial and temporal predictions of streamflow, suggesting that a multi-site calibration strategy is necessary to accurately predict spatial variation in watershed hydrology. Compared with past streamflow records, predicted future streamflow based on climate change scenarios will tend to increase in the winter but decrease in the summer. According to 26 GCM projections, annual streamflows from 2051 – 2060 (2086–2095) are projected to decrease up to 45.2% (61.3%), 48.7% (49.8%), 48.7% (56.6%), and 41.1% (44.6%) in the RRW, IRW, KRW, and WRW, respectively. In addition, under the projected changes in climate, intra- and inter-annual streamflow variability generally does not increase over time. Results suggest that increased temperature could change the rate of evapotranspiration and the form of precipitation, subsequently influencing monthly streamflow patterns. Moreover, the spatially varying pattern of streamflow variability under future climate conditions suggests different buffering capabilities among regions. As such, regionally specific management strategies are necessary to mitigate the potential impacts of climate change and preserve aquatic ecosystems and water resources.