SPAtially Referenced Regression on Watershed models developed for the Upper Midwest were used to help evaluate the nitrogen-load reductions likely to be achieved by a variety of agricultural conservation practices in the Upper Mississippi-Ohio River Basin (UMORB) and to compare these reductions to the 45% nitrogen-load reduction proposed to remediate hypoxia in the Gulf of Mexico (GoM). Our results indicate that nitrogen-management practices (improved fertilizer management and cover crops) fall short of achieving this goal, even if adopted on all cropland in the region. The goal of a 45% decrease in loads to the GoM can only be achieved through the coupling of nitrogen-management practices with innovative nitrogen-removal practices such as tile-drainage treatment wetlands, drainage–ditch enhancements, stream-channel restoration, and floodplain reconnection. Combining nitrogen-management practices with nitrogen-removal practices can dramatically reduce nutrient export from agricultural landscapes while minimizing impacts to agricultural production. With this approach, it may be possible to meet the 45% nutrient reduction goal while converting less than 1% of cropland in the UMORB to nitrogen-removal practices. Conservationists, policy makers, and agricultural producers seeking a workable strategy to reduce nitrogen export from the Corn Belt will need to consider a combination of nitrogen-management practices at the field scale and diverse nitrogen-removal practices at the landscape scale.