Based on the latest CMIP6 global climate model, the climate and runoff changes in the Poyang Lake Basin in the middle of the 21st century (2050-2062) under various model scenarios were assessed. The SWAT model was constructed based on the hydrometeorological and underlying surface data in the Poyang Lake Basin from 2001 to 2019, and four climate models of CMIP6 were used to construct future climate scenarios using Delta downscaling method and simulate hydrological processes. The results show that compared with the reference period (2002-2014), the precipitation and temperature of the basin under various model scenarios have an increasing trend, and the simulated evapotranspiration and runoff also increase, while the increase of runoff in the downstream areas of the basin is greater than that in other regions. The temperature increase under the SSP585 scenario is greater than that under the SSP126 scenario, and the runoff under the SSP585 scenario is less than that under the SSP126 scenario. Although the climate gets warmer still in the future, which leads to the increasing evapotranspiration in the basin, the variation of runoff (−11.93%~49.73%) is larger than that of evapotranspiration (1.06%~11.71%), which results in more occurrence of extreme hydrologic events. The results of climate change and hydrological processes can guide water resources management and decision making for the Poyang Lake Basin.