Understanding the physical processes of point source (PS) and nonpoint source (NPS) pollution is critical to evaluate river water quality and identify major pollutant sources in a watershed. In this study, we used the physically-based hydrological/water quality model, Soil and Water Assessment Tool, to investigate the influence of PS and NPS pollution on the water quality of the East River (Dongjiang in Chinese) in southern China. Our results indicate that NPS pollution was the dominant contribution (>94%) to nutrient loads except for mineral phosphorus (50%). A comprehensive Water Quality Index (WQI) computed using eight key water quality variables demonstrates that water quality is better upstream than downstream despite the higher level of ammonium nitrogen found in upstream waters. Also, the temporal (seasonal) and spatial distributions of nutrient loads clearly indicate the critical time period (from late dry season to early wet season) and pollution source areas within the basin (middle and downstream agricultural lands), which resource managers can use to accomplish substantial reduction of NPS pollutant loadings. Overall, this study helps our understanding of the relationship between human activities and pollutant loads and further contributes to decision support for local watershed managers to protect water quality in this region. In particular, the methods presented such as integrating WQI with watershed modeling and identifying the critical time period and pollutions source areas can be valuable for other researchers worldwide.