The negative effects of nutrient pollution in streams, rivers, and downstream waterbodies remain widespread global problems. Understanding the cost-effectiveness of different strategies for mitigating nutrient pollution is critical to making informed decisions and defining expectations that best utilize limited resources, which is a research priority for the US Environmental Protection Agency. To this end, we modeled nutrient management practices including residue management, cover crops, filter strips, grassed waterways, constructed wetlands, and reducing fertilizer in the upper East Fork of the Little Miami River, an 892 km2 watershed in southwestern Ohio, United States. The watershed is 64% agriculture with 422 km2 of row crops contributing an estimated 71% of the system's nutrient load. The six practices were modeled to treat row crop area, and among them, constructed wetlands ranked highest for their low costs per kilogram of nutrient removed. To meet a 42% phosphorus (P) reduction target for row crops, the model results suggested that the runoff from 85.5% of the row crop area would need to be treated by the equivalent of 3.61 km2 of constructed wetlands at an estimated cost of US$2.4 million annually (or US$48.5 million over a 20-year life cycle). This prompted a series of projects designed to understand the feasibility (defined in terms of build, treatment, and cost potential) of retrofitting the system with the necessary extent of constructed wetlands. The practicalities of building this wetland coverage into the system, while leading to innovation in unit-level design, has highlighted the difficulty of achieving the nutrient reduction target with wetlands alone. Approximately US$1.2 million have been spent on constructing 0.032 km2 of wetlands thus far and a feasibility analysis suggests a cost of US$38 million for an additional 0.409 km2. However, the combined expenditures would only achieve an estimated 13% of the required treatment. The results highlight the potential effectiveness of innovative design strategies for nutrient reduction and the importance of considering realistic field-scale build opportunities, which include accounting for acceptance among landowners, in watershed-scale nutrient reduction simulations using constructed wetlands.