The Zayandeh-Rud River basin, Iran, is projected to face spatiotemporally heterogeneous temperature increase and precipitation reduction that will decrease water supply by mid-century. With projected increase (0.70–1.03 °C) in spring temperature and reduction (6–55%) in winter precipitation, the upper Zayandeh-Rud sub-basin, the main source of renewable water supply, will likely become warmer and drier. In the lower sub-basin, 1.1–1.5 °C increase in temperature and 11–31% decrease in annual precipitation are likely. A system dynamics model was used to analyze adaptation strategies taking into account feedbacks between water resources development and biophysical and socioeconomic sub-systems. Results suggest that infrastructural improvements, rigorous water demand management (e.g., replacing high water demand crops such as rice, corn, and alfalfa), and ecosystem-based regulatory prioritization, complemented by supply augmentation can temporarily alleviate water stress in a basin that is essentially governed by the Limits to Growth archetype.