Agricultural non–point source (NPS) pollution poses a severe threat to water quality and aquatic ecosystems. In response, tremendous efforts have been directed toward reducing these pollution inputs by implementing agricultural conservation practices. Although conservation practices reduce pollution inputs from individual fields, scaling pollution control benefits up to the watershed level (i.e., improvements in stream water quality) has been a difficult challenge. This difficulty highlights the need for NPS reduction programs that focus efforts within target watersheds and at specific locations within target watersheds, with the ultimate goal of improving stream water quality. Fundamental program design features for NPS control programs—i.e., number of watersheds in the program, total watershed area, and level of effort expended within watersheds—have not been considered in any sort of formal analysis. Here, we present an optimization model that explores the programmatic and environmental trade-offs between these design choices. Across a series of annual program budgets ranging from $2 to $200 million, the optimal number of watersheds ranged from 3 to 27; optimal watershed area ranged from 29 to 214 km²; and optimal expenditure ranged from $21,000 to $35,000/km². The optimal program configuration was highly dependent on total program budget. Based on our general findings, we delineated hydrologically complete and spatially independent watersheds ranging in area from 20 to 100 km². These watersheds are designed to serve as implementation units for a targeted NPS pollution control program currently being developed in Wisconsin.