Excess anthropogenic use of synthetic fertilizers since the mid-20th century has increased loading of nitrogen and other nutrients to the Gulf of Mexico from the Mississippi River leading to hypoxic waters and marine ecosystem stress, a problem commonly repeated around the globe. Wetland restoration is a viable intervention that reduces nutrient loading from the basin to coastal waters; however, the magnitude of export reduction estimated from prior studies may not fully reflect the mechanisms that contribute to N retention, including hydrologic connectivity and seasonality. Here, we apply a simulation framework to systematically explore the role of sub-annual seasonality, engineering constraints, and primary mechanistic uncertainties surrounding field-margin wetland restoration. Dynamic flow and lower spring water temperatures coinciding with the largest seasonal pulse of nitrogen leachate reduced nitrogen removal efficiency by approximately 20%. A systematic evaluation of the role of engineering constraints, and limited supply of nitrogen leachate from some croplands where wetland restoration is possible suggests that wetland restoration alone would be incapable of reducing nitrogen export to established targets. High fluxes of whole-basin nitrogen removal through wetland denitrification reported in previous studies reflect hydrologic connectivity between crop leachate sources and potentially restorable areas that may be source-limited in practice. We find that sufficiently reducing loading to protect the Gulf of Mexico, while maximizing crop production, would require more expansive and extensive of interventions beyond wetland restoration alone, though it would remain an important element in any plan to dramatically reduce nitrogen export to marine ecosystems.