With the continuous enhancement of point source pollution control, non-point source (NPS) pollution has become an important factor in the deterioration of surface water quality. Meanwhile, due to the soaring global population, long-term effects of anthropogenic factors on non-point source pollution in large river basins have increasingly attracted worldwide attention. The Yangtze river is the largest river basin of China, and protecting its ecological environment has great significance on protecting the lifeline of the entire Yangtze river. In this study, the improved output coefficient and nutrient losses empirical model were used to conduct space–time simulations of non-point source pollution in the upper reaches of the Yangtze river (URYR) based on GIS during 1960–2003. This method reveals the anthropogenic effects of non-point source pollution in the upper reaches of the Yangtze river. The results indicate that the impacts of anthropogenic factors on dissolved pollutants increased significantly, while those on sediment and adsorbed pollutants increased first and then decreased during the simulation year. Agricultural land use and atmospheric deposition, as well as rural life, were the main sources of dissolved pollutants. In addition, dry land and paddy fields were the major sources of sediment and adsorbed pollutants. For the load intensities, the long-term effects of anthropogenic factors on dissolved pollutants increased rapidly, and those on the load intensity of sediment and adsorbed pollutants increased first and then decreased. Therefore, the study would propose some corresponding environmental management measures to strengthen environmental protection and non-point source pollution control in the upper reaches of the Yangtze river.