At present, little is known about the linkages between climate variability, riverine nutrient fluxes, and coastal marine eutrophication. It was observed that short-term climate anomalies, such as droughts and floods, may substantially alter nutrient delivery to the coastal ocean, and influence surface net productivity, vertical flux of carbon, and oxygen depletion in bottom waters. The northern Gulf of Mexico, which is strongly affected by the Mississippi River, the sixth world largest river, provides ample opportunity to study such influences. Here, we use a coupled physical-biological model to examine the coupling between decadal changes in the Mississippi River nutrient fluxes and coastal eutrophication near the Mississippi River Delta. The model is based on a dual-budget approach that uses stable oxygen isotopes in addition to conventional oxygen concentration measurements. Model simulations suggest that bottom water hypoxia intensified about thirty years ago, as a probable consequence of increased net productivity and increased sedimentation of the organic material produced in the upper water column. Apparently, long-term increase in riverine nutrient fluxes has been responsible for this historical decrease in bottom layer oxygen concentrations. Nevertheless, the influence of climatic factors has been significant and may further increase as a result of global climate change. Importantly, model simulations are in good agreement with the available historical data from the northern Gulf of Mexico, and are additionally supported by the retrospective analyses of sedimentary records.