Water resources scarcity has threatened the coordinative development of demographics, society and economy. As a typical rapidly urbanizing area and an emerging megacity in China, Chengdu is confronting the pressure of inadequate water supply. The present study divides the macroeconomic factors that affect the water resource supply and demand balance into six major subsystems: water resources supply, water demand, water drainage, population, ecological environment and economy. The combining variable interaction description and predictive simulation models are applied to simulate the water supply and demand ratio (S:D) from 2005 to 2035. Further, this study designs different development scenarios to simulate the change of S:D ratios by altering the parameter values of driving factors. The results show that: (1) the S:D ratio will decline if the current development scenario continues, implying the serious water resources shortage and the severe water supply-demand conflict in Chengdu; (2) socio-economic water demand and wastewater/rainwater reuse are the key driving parameters of S:D ratio, especially the water consumption per ten thousand yuan of industrial value-added; (3) the S:D ratio will increase from 0.92 in the current baseline scenario to 1.06 in the integrated optimization scenario in 2025, and the long-term planning brings 2035 from 0.71 to 1.03, with the proportion of unconventional water supply rise to 38% and 61%, respectively. This study can provide a decision-making tool for policy-makers to explore plausible policy scenarios necessary for bridging the gap between the water supply and demand in megacities.