An increasing global population and growing wealth are raising demand for energy and food, impacting on the environment and people living in river basins. Sectoral decision-making may not optimize socio-economic benefits because of perverse impacts in other sectors for people and ecosystems. The hydropower–food supply nexus in the Mekong River basins is assessed here in an influence model. This shows how altering one variable has consequent effects throughout the basin system. Options for strategic interventions to maximize benefits while minimizing negative impacts are identified that would enable national and sub-national policy makers to take more informed decisions across the hydropower, water and food supply sectors. This approach should be further tested to see if it may aid policy making in other large river systems around the world.