Climate change could add a variety of uncertainties to hydrological processes and water resources. Very limited efforts have been devoted to applying the US-EPA (Environmental Protection Agency)’s Hydrologic and Water Quality System (HAWQS) model for predicting climate change impacts on hydrological processes at basin scale. Here we applied the model to project the next 50 years’ (from 2021 to 2070) hydrological processes at the Yazoo River basin in Mississippi, USA. Simulations showed that over the next 50 years, there are no significant trends in monthly precipitation, ET, runoff, and discharge; only 2% of the annual precipitation percolated into the deep aquifer; and dry seasons become dryer and wet seasons become wetter. These findings provide very useful information to stakeholders for water resource management. Our study further suggests that the HAWQS model is a user friendly and time-saving tool for basin scale hydrological modeling.