The climatic processes such as changes in precipitation, temperature and atmospheric CO2 concentration can intensify the effects on water resources. An assessment of the effects of long-term climate change on water resources is essential to the development of water quality improvement programs. This study was conducted in the Upper Pearl River Watershed (UPRW) in east-central Mississippi to assess the effects of long-term potential future climate change on average mean monthly stream flow from the five spatially distributed U. S. Geological Survey (USGS) gage stations in the UPRW using the Soil and Water Assessment Tool. The model was calibrated (January 1981 to December 1994) and validated (January 1995 to September 2008) using monthly measured stream flow data. The calibrated and validated model determined good to very good performance for stream flow prediction (R2 and E from 0·60 to 0·86) between measured and predicted stream flow values. The root mean square error values (from 14 to 37 m3 s−1) were estimated at similar levels of errors during model calibration and validation. The results showed that long-term (50 years) average monthly stream flow sensitivity due to climate change effects was found the greatest as a result of percentage change in the precipitation followed by carbon dioxide (CO2) concentration and temperature. The long-term model simulation scenarios as compared with the base scenario for all five spatially distributed USGS gage stations in the UPRW estimated an average monthly stream flow decrease (from 54 to 67%) and average monthly stream flow increase (from 67 to 79%) depending on the spatial characteristics of the USGS gage stations. Overall, the results indicate that the UPRW hydrology is very sensitive to potential future climate changes and that these changes could stimulate increased streamflow generation from the watershed. Copyright © 2010 John Wiley & Sons, Ltd.