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Abstract Reducing nutrient loss from agriculture to improve water quality requires a combination of management practices. However, it has been unclear what pattern of mitigation is likely to emerge from different policies, individually and combined, and the consequences for local and national land use and farm returns. We address this research gap by constructing an integrated multi-scale framework for evaluating alternative nitrogen loss management policies for corn production in the US. This approach combines site- and practice-specific agro-ecosystem processes with a grid-resolving economic model to identify locations that can be prioritized to increase the economic efficiency of the policies. We find that regional measures, albeit effective in reducing local nitrogen loss, can displace corn production to the area where nitrogen fertilizer productivity is low and nutrient loss rate is high, thereby offsetting the overall effectiveness of the nutrient management strategy. This spatial spillover effect can be suppressed by implementing the partial measures in tandem with nationwide policies. Wetland restoration combined with split fertilizer application, along with a nitrogen loss tax could reduce nitrate nitrogen loss to the Mississippi River by 30% while only increasing corn prices by less than 2%.