Intensively managed row crop agriculture has fundamentally changed Earth surface processes within the Mississippi River basin through large-scale alterations of land cover, hydrology and reactive nitrogen availability. These changes have created leaky landscapes where excess agriculturally derived nitrate degrades riverine water quality at local, regional and continental scales. Individually, wetlands are known to remove nitrate but the conditions under which multiple wetlands meaningfully reduce riverine nitrate concentration have not been established. Only one region of the Mississippi River basin—the 44,000 km2 Minnesota River basin—still contains enough wetland cover within its intensively agriculturally managed watersheds to empirically address this question. Here we combine high-resolution land cover data for the Minnesota River basin with spatially extensive repeat water sampling data. By clearly isolating the effect of wetlands from crop cover, we show that, under moderate-high streamflow, wetlands are five times more efficient per unit area at reducing riverine nitrate concentration than the most effective land-based nitrogen mitigation strategies, which include cover crops and land retirement. Our results suggest that wetland restorations that account for the effects of spatial position in stream networks could provide a much greater benefit to water quality then previously assumed.