The global socio-economic and agricultural expansion is accompanied by large inputs of nitrogen (N) and phosphorus (P) on land and by a serious alteration of the water cycle and water quality. The Mediterranean basin represents a paradigmatic region to study the entangled nutrient and water challenges because the region, where many of the world's climatic and socio-economic gradients are present, is predicted to suffer severe water stress in the coming decades yet at the same time agricultural intensification and population are increasing in many rim countries. We here describe the biogeochemical budgets of N and P in 549 river basins for the 2000–2009 period, analyzing how the climatic gradient and water management practices affect the fluxes of N and P and their stoichiometric ratios. Average land inputs are 3,600 kg N km−2 yr−1 and 470 kg P km−2 yr−1, with a significant variation between basins (>100 times) closely related to the stage of agricultural intensification. Moreover, the combination of aridity and water regulation can strongly alter the final balances, not only by changing the export of nutrients by rivers (riverine export is ca. 10% for N and 8% for P in arid basins), but also decoupling the N:P ratios between terrestrial and freshwater compartments.