Natural infrastructure as a mitigation measure for flooding has received increased attention following recent extreme rainfall and flood events in North Carolina. While natural infrastructure (e.g., wetlands, floodplain expansion, reforestation, etc.) has been shown to reduce runoff and mitigate peak flows, it is difficult to predict the aggregate impacts of widespread implementation at the watershed scale for a given location. The primary objectives of this study were to identify suitable areas for natural infrastructure implementation on the landscape to reduce flooding and to use the Soil & Water Assessment Tool (SWAT) model to simulate the flood reduction and water quality impacts for three subwatersheds (~150 sq. km each) of the Neuse River Basin. Model results indicated that substantial localized annual maximum flow reduction (up to 30–40%) was possible, mostly correlated to the area of natural infrastructure implementation in the subbasin, but flood reduction benefits declined at the subwatershed-scale (1–16%). On a per hectare basis, wetlands sized and designed strategically for flood control had a greater impact on peak flow reduction than reforestation. The implementation of reforestation and flood control wetlands produced substantial nutrient and sediment load reductions, which also correlated with the area of natural infrastructure implementation. Total nitrogen load reduction ranged from 6 to 18% and total phosphorus load reductions from 4 to 17% for the most intensive implementation of wetlands restoration and reforestation. Sediment load reductions ranged from 16 to 30%. The results of this study illustrate that while flood reduction benefits can be realized at local scales (i.e., subbasin), a substantial area would need to be converted to natural infrastructure to provide flood reduction benefits at the watershed scale.