A seasonally occurring summer hypoxic (low oxygen) zone in the northern Gulf of Mexico is the second largest in the world. Reductions in nutrients from agricultural cropland in its watershed are needed to reduce the hypoxic zone size to the national policy goal of 5,000 km² (as a 5-y running average) set by the national Gulf of Mexico Task Force’s Action Plan. We develop an integrated assessment model linking the water quality effects of cropland conservation investment decisions on the more than 550 agricultural subwatersheds that deliver nutrients into the Gulf with a hypoxic zone model. We use this integrated assessment model to identify the most cost-effective subwatersheds to target for cropland conservation investments. We consider targeting of the location (which subwatersheds to treat) and the extent of conservation investment to undertake (how much cropland within a subwatershed to treat). We use process models to simulate the dynamics of the effects of cropland conservation investments on nutrient delivery to the Gulf and use an evolutionary algorithm to solve the optimization problem. Model results suggest that by targeting cropland conservation investments to the most cost-effective location and extent of coverage, the Action Plan goal of 5,000 km² can be achieved at a cost of $2.7 billion annually. A large set of cost-hypoxia tradeoffs is developed, ranging from the baseline to the nontargeted adoption of the most aggressive cropland conservation investments in all subwatersheds (estimated to reduce the hypoxic zone to less than 3,000 km² at a cost of $5.6 billion annually).