This paper looks at regional water security in eastern China in the context of global climate change. The response of runoff to climate change in the Qinhuai River Basin, a typical river in eastern China, was quantitatively investigated by using the Soil and Water Assessment Tool (SWAT) model and the ensemble projection of multiple general circulation models (GCMs) under three different shared socioeconomic pathways (SSPs) emission scenarios. The results show that the calibrated SWAT model is applicable to the Qinhuai River Basin and can accurately characterize the runoff process at daily and monthly scales with the Nash–Sutcliffe efficiency coefficients (NSE), correlation coefficients (R), and the Kling–Gupta efficiency (KGE) in calibration and validation periods being above 0.75 and relative errors (RE) are ±3.5%. In comparison to the baseline of 1980–2015, the mean annual precipitation in the future period (2025–2060) under the three emission scenarios of SSP1-2.6, SSP2-4.5, and SSP5-8.5 will probably increase by 5.64%, 2.60%, and 6.68% respectively. Correspondingly, the multiple-year average of daily maximum and minimum air temperatures are projected to rise by 1.6–2.1 °C and 1.4–2.0 °C, respectively, in 2025–2060. As a result of climate change, the average annual runoff will increase by 16.24%, 8.84%, and 17.96%, respectively, in the period of 2025–2060 under the three SSPs scenarios. The increase in runoff in the future will provide sufficient water supply to support socioeconomic development. However, increases in both rainfall and runoff also imply an increased risk of flooding due to climate change. Therefore, the impact of climate change on flooding in the Qinhuai River Basin should be fully considered in the planning of flood control and the basin’s development.
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