Based on the long-term observation data of Poyang Lake, various mathematical statistical methods were used to explore the trend, mutation, and periodic characteristics of the hydrological regime evolution, and the fluctuation process of water quality was analyzed by selecting the indicators of permanganate index, ammonia nitrogen, and total phosphorus. Moreover, the driving effects of different hydrological parameters on water quality were analyzed. The results show that the water level of Poyang Lake has generally decreased from 1962 to 2022, with an average rate of change of -0.013 5 m/a, and the abrupt change year is concentrated around 2003, with a water level change cycle of about 36 years; the water quality shows a decreasing-and-then-stabilizing trend from 1988 to 2022, with total phosphorus as the main exceedance factor, and the exceedance multiples range from 0.02 to 2.31; the slight fluctuating trend of water quality indicators at each station since 2015 is expected to continue in the future at most stations; the permanganate index is weakly correlated with hydrological parameters, and ammonia nitrogen and total phosphorus are significantly correlated with many hydrological parameters. The water level is the main factor influencing the concentration of nitrogen and phosphorus. Water temperature, precipitation amount, and inflow volume of water have significant regulatory effects on water quality changes. Water level changes have a significant unidirectional effect on ammonia nitrogen and a relatively complex effect on total phosphorus.