The provision of reliable water resources, safe grain production, and sustainable energy supply can be deemed as key guarantees for economic growth and human living improvement, but which have been challenged by imbalance relationship between increasing demand and limited supply capacity. In this study, a sustainable water-food-energy plan has been developed to conduct an optimal framework into a multiple water-reservoir system for confronting regional natural and artificial damages such as water deficit, food crisis and electric insufficient contemporarily. A simulation-optimization approach has been proposed to handle multiple uncertainties due to climatic and socioeconomic changes. The proposed approach has advantages of reflecting the climatic change in a lumped and conceptual way; meanwhile, it is effective to deal with socioeconomic uncertainties regarded as probability and possibility distributions, reducing the risk of decision-making with Green criterions. The developed water-food-energy plan with simulation-optimization approach can be applied to a real case study of Jing River, China. The obtained results of water-food-energy shortage, optimal water allocation-food production energy generation, flood control, and system benefit under various policy-scenarios can be identify comprehensive water-food-energy alternatives in a multi-reservoir optimization system. Meanwhile, the results associated with credibility confidence, risk-averse attitude parameter and robustness coefficient can support the generation of a water-food-energy plan with a robust manner. It can support the improvement of water supply, irrigative production, energy generation, industrial pattern adjustment, flood risk control, supply capacity at a regional view, with aim to achieve sustainability of human activities and resource-energy conservation.