Major rivers in developing and emerging countries suffer increasingly of severe degradation of water quality. The current study uses a mathematical Material Flow Analysis (MMFA) as a complementary approach to address the degradation of river water quality due to nutrient pollution in the Thachin River Basin in Central Thailand. This paper gives an overview of the origins and flow paths of the various point- and non-point pollution sources in the Thachin River Basin (in terms of nitrogen and phosphorus) and quantifies their relative importance within the system. The key parameters influencing the main nutrient flows are determined and possible mitigation measures discussed. The results show that aquaculture (as a point source) and rice farming (as a non-point source) are the key nutrient sources in the Thachin River Basin. Other point sources such as pig farms, households and industries, which were previously cited as the most relevant pollution sources in terms of organic pollution, play less significant roles in comparison. This order of importance shifts when considering the model results for the provincial level. Crosschecks with secondary data and field studies confirm the plausibility of our simulations. Specific nutrient loads for the pollution sources are derived; these can be used for a first broad quantification of nutrient pollution in comparable river basins. Based on an identification of the sensitive model parameters, possible mitigation scenarios are determined and their potential to reduce the nutrient load evaluated. A comparison of simulated nutrient loads with measured nutrient concentrations shows that nutrient retention in the river system may be significant. Sedimentation in the slow flowing surface water network as well as nitrogen emission to the air from the warm oxygen deficient waters are certainly partly responsible, but also wetlands along the river banks could play an important role as nutrient sinks.