Optimal reservoir operation changes and adaptation strategies for the Zayandeh-Rud River Basin's surface water supply system are examined for a changing climate during the 2015–2044 period. On average, the monthly temperature in the basin is expected to increase by 0.46–0.76 °C and annual precipitation is expected to decrease by 14–38% with climate change, resulting in a reduction of the Zayandeh-Rud's peak stream flow and the amplitude of its seasonal range. Snowfall decrease in winter months will generally lead to an 8–43% reduction in annual stream flow under climate change. A reservoir operation model is developed and optimal reservoir operation strategies are identified for adaptation of the basin's surface water supply to climate change in the face of the increasing water demand. Results indicate that the reservoir drawdown season starts 2 months earlier under climate change. Smaller storage levels and greater water releases must occur to meet the increasing water demand. The optimized water release can provide sufficient water for non-agricultural water demand, but agriculture will experience more severe water shortage under a changing climate. Having the highest vulnerability, the agricultural sector should be the main focus of regional management plans to address the current water challenge and more severe water shortages under climate change.