The endorheic basin of Zayandehrud in Iran suffers from environmental problems, social tensions, and economic instability. Lack of understanding how the water system and the socio-economic system interact may explain these challenges. A system dynamics model, being a holistic simulation tool, was developed for the Zayandehrud basin and used to evaluate several policy scenarios. The indices of employment, gross regional product, the volume of groundwater and surface water stored, flow into the basin’s end lake, and the water flow in the river were used to evaluate the scenarios. The findings demonstrate that focusing on supply-based activities or water demand management cannot solely improve the condition of the Zayandehrud basin. It is required to reconsider the development policies of the region in a broader context. Reducing the irrigated area by 15% and developing new industries up to a certain limit may make the combined water and socio-economic system sustainable.