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Reducing the size of the hypoxic zone in the Gulf of Mexico has proven to be a challenging task. A variety of mitigation options have been proposed, each likely to produce markedly different patterns of mitigation with widely varying consequences for the economy. The general consensus is that no single measure alone is sufficient to achieve the EPA Task Force goal for reducing the Gulf hypoxic zone and it appears that a combination of management practices must be employed. However, absent a highly resolved, multi-scale framework for assessing these policy combinations, it has been unclear what pattern of mitigation is likely to emerge from different policies and what the consequences would be for local, regional and national land use, food prices and farm returns. We address this research gap by utilizing a novel multi-scale framework for evaluating alternative N loss management policies in the Mississippi River basin. This combines fine-scale agro-ecosystem responses with an economic model capturing domestic and international market and price linkages. We find that wetland restoration combined with improved N use efficiency, along with a leaching tax could reduce the Mississippi River N load by 30-53\% while only modestly increasing corn prices. This study underscores the value of fine-resolution analysis and the potential of combined economic and ecological instruments in tackling nonpoint source nitrate pollution.