The Lot river, a major tributary of the downstream Garonne river, the largest river on the Northern side of the Pyrenees Mountains, was intensively studied in the 1970s. A pioneering program called “Lot Rivière Claire” provided a diagnosis of water quality at the scale of the whole watershed and proposed an ambitious program to manage nutrient pollution and eutrophication largely caused by urban wastewater releases. Later on, the implementation of European directives from 1991 to 2000 resulted in the nearly complete treatment of point sources of pollution in spite of a doubling of the basin’s population. At the outlet of the Lot river, ammonium and phosphate contamination which respectively peaked to 1 mg N-NH4 L−1 and 0.3 mg P-PO4 L−1 in the 1980s returned to much lower levels in recent years (0.06 mg N-NH4 L−1 and 0.02 mg P-PO4 L−1), a reduction by a factor 15. However, during this time, nitrate contamination has regularly increased since the 1980s, from 0.5 to 1.2 mg N-NO3 L−1 in average, owing to the intensification of agriculture and livestock farming. Application of the Riverstrahler model allowed us to simulate the water quality of the Lot drainage network for the 2002–2014 period. We showed that, with respect to algal requirements, phosphorus and silica are well balanced, but nitrogen remains largely in excess over phosphorus and silica. This imbalance can be problematic for the ecological status of the water bodies. Using the model, for simulating various scenarios of watershed management, we showed that improvement of urban wastewater treatment would not result in any significant change in the river’s water quality. Even though arable land occupies a rather limited fraction of the watershed area, only the adoption of better farming practices or more radical changes in the agro-food system could reverse the trend of increasing nitrate contamination.