Managers of large river basins face conflicting needs for water resources such as wildlife habitat, water supply, wastewater assimilative capacity, flood control, hydroelectricity, and recreation. The Savannah River Basin for example, has experienced three major droughts since 2000 that resulted in record low water levels in its reservoirs, impacting local economies for years. The Savannah River Basin’s coastal area contains municipal water intakes and the ecologically sensitive freshwater tidal marshes of the Savannah National Wildlife Refuge. The Port of Savannah is the fourth busiest in the United States, and modifications to the harbor have caused saltwater to migrate upstream, reducing the freshwater marsh’s acreage more than 50 percent since the 1970s. There is a planned deepening of the harbor that includes flow-alteration features to minimize further migration of salinity. The effectiveness of the flow-alteration features will only be known after they are constructed. One of the challenges of basin management is the optimization of water use through ongoing development, droughts, and climate change. This paper describes a model of the Savannah River Basin designed to continuously optimize regulated flow to meet prioritized objectives set by resource managers and stakeholders. The model was developed from historical data by using machine learning, making it more accurate and adaptable to changing conditions than traditional models. The model is coupled to an optimization routine that computes the daily flow needed to most efficiently meet the water-resource management objectives. The model and optimization routine are packaged in a decision support system that makes it easy for managers and stakeholders to use. Simulation results show that flow can be regulated to significantly reduce salinity intrusions in the Savannah National Wildlife Refuge while conserving more water in the reservoirs. A method for using the model to assess the effectiveness of the flow-alteration features after the deepening also is demonstrated