Non-point source (NPS) pollution has been increasingly recognized as a major contributor to the declining quality of aquatic environment in recent years. Because of the data shortage, the non-point source loads estimation in the large-scale watershed is always difficult in most developing countries. In this study, small-scale watershed extended method (SWEM) was introduced with a case study in the middle part of Three Gorges Reservoir Region (TGRR). Small-scale watershed extended method is the method which uses physical-based models in some small typical catchments of the targeted large watershed, and then the parameters obtained from those small catchments are extended to the surrounding area until the non-point source pollution loads in the entire watershed or region are obtained. The selected small catchments should have sufficient data. Here, the middle part of the Three Gorges Reservoir Region, about 12,500 km2, was chosen as the targeted region for the case study. In this region, considering the data availability, Xiaojiang River was screened as a typical watershed and was simulated with Soil and Water Assessment Tool model through accurate parameter calibration and validation. And then the parameter group obtained in Xiaojiang River Watershed was extended to the entire study area to quantify the total non-point source pollution loads. After which, the spatio-temporal characteristics of the non-point source pollution in the middle part of the Three Gorges Reservoir Region were analyzed, as well as the pollution from each tributary and different under layer surface conditions. The small-scale watershed extended method provides a practical approach for non-point source pollution loads estimation in the large-scale watershed or region.