Reducing the quantity of water in recent years has increased the competition between development projects and the environment. Wetlands are increasingly under pressure due to human activities. The most serious threats to wetlands are excessive agriculture and the diversion of water for irrigation. In recent years, due to water shortage and drought, wetland dryness in Iran has caused many problems, including the dust crisis. Therefore, planning at the basin scale is necessary to achieve sustainable development, which emphasizes the employment of mathematical models. In this study, using a reliability-based simulation–optimization approach, development planning in the Karkheh basin with the following two objectives is investigated: (1) total area under cultivation of agricultural development sectors and (2) supply reliability of the environmental flow requirement. The Water Evaluation and Planning (WEAP) model is used for the simulation of water resources and the multi-objective particle swarm optimization (MOPSO) algorithm is employed for optimization. The results show that in addition to significantly improving the supply reliability of the wetland requirement (from 55 to 79%), the design of agricultural development projects has been optimized. The reliability-based model has prevented unsustainable developments in the basin. Also, the average supply reliability of agricultural demands has increased from 51% (in previous studies) to 72%.