The study was carried out at 4 vertical water layers among the 0-20 m water layer of 7 horizontal monitoring stations seasonally during May 2017-October 2019 in Danjiangkou Reservoir of the Middle Route Project of South to North Water Diversion in China, and explored the key drivers of the changes in chlorophyll-a (Chl.a) along with different water layers of different sampling stations. Based on the trophic state index (TSI), we found that all sites in the Danjiangkou Reservoir were mesotrophic water bodies. We found a trend of increase in Chl.a concentration in the Danjiangkou Reservoir, and the extreme concentrations were likely increasing yearly. The nutrient and Chl.a concentration showed temporal and spatial changes in the Danjiangkou Reservoir. The upstream of the reservoir area has higher total phosphorus and ammonia nitrogen concentrations, the Hanjiang Reservoir has the highest Chl.a concentration. Therefore, source pollution control and monitoring are still the top priority of Danjiangkou Reservoir management. The important drivers of Chl.a concentration varied among different sites. The Chl.a concentration in the upstream of Hanjiang River and the dam area are affected by nitrate nitrogen and pH, respectively, while the dam site of the outlet is mainly affected by water depth, water temperature and ammonia nitrogen. The Chl.a concentration in the upstream of Danjiang Reservoir is affected by water depth, nitrogen nutrients, total phosphorus and water temperature, but the Chl.a concentration in the Danjiangkou Reservoir was mainly affected by water depth and organic matter input. Therefore, the management of each site of the Danjiangkou Reservoir should be divided into different ecological zones and adopt the right management measurements. This study aims to provide basic ecological data for the sustainable ecological scheduling of the South-to-North Water Diversion Middle Route Project and provide a theory for improving the management of reservoirs.