Lake Hongze is an important storage lake for the eastern route of the South-to-North Water Diversion Project. To assess the long-term changes in water quality, 16 monitoring sites were deployed based on environmental heterogeneity. Monthly water quality monitoring was carried out from 2012 to 2018 to examine the long-term trend of the water quality of Lake Hongze and the effects of hydrometeorological factors on the changes in nutrients. The results showed that from 2012 to 2018, the average annual concentrations of total nitrogen, total phosphorus, and transparency in Lake Hongze were 1.74 mg/L (Grade V), 0.081 mg/L (Grade IV), and 0.48 m, respectively, without significant decline trend. In contrast, the average annual concentrations of permanganate index and chlorophyll-a were 4.13 and 0.008 mg/L, respectively, presenting a significant decrease trend. In terms of spatial patterns, the concentration of total nitrogen and total phosphorus in the flushing area was higher than that of Chengzi Bay and Lihewa Bay; while the permanganate index and chlorophyll-a concentration were relatively lower. The concentration of permanganate index in Chengzi Bay and Lihewa Bay decreased significantly, which was significantly different from the water quality change trend of the flushing area. The concentration of chlorophyll-a in all three regions of the lake decreased significantly. The results of correlation analysis showed that the total nitrogen and total phosphorus in Lake Hongze strongly correlated with the water quality of the Huaihe River, especially in the flushing area. The correlation between the water quality of Lihewa Bay and the water quality of Huaihe River is quite weak. The generalized additive model (GAM) showed that the water quality and suspended solids concentration of the flushing area was significantly correlated to the change of water quality in Huaihe River, and the factors influencing the water quality of Chengzi Bay and Lihewa Bay varied greatly. The relationships between chlorophyll-a and permanganate index in Chengzi Bay and flushing area were relatively strong, while the concentration of chlorophyll-a in Lihewa Bay was significantly related to precipitation and transparency. The correlation and GAM model indicated that the Huaihe River imposed profound effects on the water quality of Lake Hongze, especially in the flushing area, which may be an important driver in maintaining a higher nutrient level and spatial differentiation of water quality in Lake Hongze. The decreasing trend of chlorophyll-a concentration in different regions indicated that the trophic status of Lake Hongze has decreased. Routine monitoring, pollutants reduction, aquaculture control should be implemented to ensure the safety of water quality in Lake Hongze.