The water quality in the Danjiangkou Reservoir has attracted considerable attention from the Chinese public and govment since the announcement of the Middle Route of the South to North Water Diversion Project (SNWDP), which commenced transferring water in 2014. Integrated research on the evaluation, prediction, and protection of water quality in the Danjiangkou Reservoir was carried out in this study in order to improve environmental management. Based on 120 water samples, wherein 17 water quality indices were measured at 20 monitoring sites, a single factor evaluation method was used to evaluate the current status of water quality. The results show that the main indices influencing the water quality in the Danjiangkou Reservoir are total phosphorus (TP), permanganate index (CODMn), dissolved oxygen (DO), and five-day biochemical oxygen demand (BOD5), and the concentrations of TP, BOD5, ammonia nitrogen (NH3eN), CODMn, DO, and anionic surfactant (Surfa) do not reach the specified standard levels in the tributaries. Seasonal ManneKendall tests indicated that the CODMn concentration shows a highly significant increasing trend, and the TP concentration shows a significant increasing trend in the Danjiangkou Reservoir. The distri-bution of the main water quality indices in the Danjiangkou Reservoir was predicted using a two-dimensional water quality numerical model, and showed that the sphere of influence from the tributaries can spread across half of the Han Reservoir if the pollutants are not controlled. Cluster analysis (CA) results suggest that the Shending River is heavily polluted, that the Jianghe, Sihe, and Jianhe rivers are moderately polluted, and that they should be the focus of environmental remediation.