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 what are the impacts on land use and farm returns at both local and national levels. We address this research gap by developing an integrated multiscale framework that evaluates alternative nitrogen loss management policies for corn production in the United States. This approach combines site- and practice-specific agroecosystem 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, while effective at reducing nitrogen loss locally, may inadvertently displace corn production to areas where nitrogen fertilizer productivity is lower and nutrient loss rates are higher, thereby offsetting the overall effectiveness of the nutrient management strategy. This spatial spillover effect can, however, be mitigated by combining regional measures with broader nationwide policies. For instance, the combination of wetland restoration, split fertilizer application and a nitrogen loss tax could reduce nitrate nitrogen loading in the Mississippi River by 30%, with only a modest increase in corn prices (less than 2%).