South to North Water Transfer Project in China is the largest project over centuries to solve the water shortage problem in vast areas of northern China. It comprises of three routes: the eastern, central and western route and this study mainly focused on the eastern route. As water quality is the key factor for the eastern route, this paper examined the main factors influencing water quality of the main route south of the Yellow River, by investigating the point source, non-point source (diffusive source) and internal source pollutions along the main eastern route and in its drainage basins, and assessing the current water quality in the waterways. According to the complicated and combined systems of rivers and lakes in this route, one-dimensional water quantity and quality model for rivers and two-dimensional model for lakes were developed to simulate the hydrodynamic and pollutant transport processes. The numerical method and model algorithm were described. The values of model parameters were estimated by using field-monitoring data along the main route and the inverse modeling technique. Established models were employed to predict the degradations of CODMn and NH4+-N in the main stream, under the conditions of current pollution loads and different hydrologic conditions. Schemes were present for controlling total quantities of pollutants from point source and non-point source along the main route to secure water quality for the eastern route.