In response to rapid development and high demand for electricity, Cambodia has planned to build more hydropower dams. As a result, there are significant concerns for the changes in seasonal flow regimes which will result in degrading fisheries and biodiversity downstream. In this paper, we assess how a multipurpose dam affects downstream flows. To predict the magnitude of flow changes, flows which were simulated using SWAT (Soil and Water Assessment Tool) and other necessary data were computed into HEC-ResSim (Reservoir Simulation) models to simulate regulated flow from the dam. Downstream flows under three different operation scenarios (full-level, low-level, and seasonal variation) were modeled to compare with the baseline flows. For low-level and seasonal variation operation scenarios of Stung Sen dam, daily and seasonal flows saw a significant change. There would be an average increase of 42% in dry season flow and an average decrease of 46% in wet season flow, with the corresponding standard deviation of 22% and 19%, respectively, at the outlet of Stung Sen basin, resulting from an operation to maximize energy production. The natural river flow in this river would be significantly changed due to this dam construction.