This study aims to project the compound impacts of climate change and human activities, including agriculture expansion and hydropower generation, on the future water availability in the Sre Pok River Basin. The five regional climate models (RCMs): ACESS, REMO2009, MPI, NorESM, CNRM were selected for the future climate projection under two scenarios i.e., RCP 4.5 and RCP 8.5. Our results reveal that the future annual rainfall is expected to decrease by 200 mm whereas the average temperature is expected to increase by 0.69°C to 4.16°C under future scenarios. The future water availability of Sre Pok River Basin was projected using soil and water assessment tool (SWAT). Next, the CROPWAT model was used to examine the irrigation water requirement and the HEC-ResSim model to simulate the hydropower generation of Buon Tuar Sarh reservoir. The future simulation indicates the decrease in future water availability, increasing demand for irrigation water and decreases in hydropower generation for the future periods. The irrigated areas are increases from 700 ha to 1500 ha as per the provincial development plan. This study also examines the present and future drought conditions of Sre Pok River via streamflow drought index (SDI). Our results expect to contribute toward supporting the planning and management of water resources for agriculture and to efficiently cope with drought conditions in the studied basin and beyond.