Increasing nitrogen concentrations in the world’s major rivers have led to over-fertilization of sensitive downstream waters. Flow through channel bed and bank sediments acts to remove riverine nitrogen through microbe-mediated denitrification reactions. However, little is understood about where in the channel network this biophysical process is most efficient, why certain channels are more effective nitrogen reactors, and how management practices can enhance the removal of nitrogen in regions where water circulates through sediment and mixes with groundwater - hyporheic zones. Here we present numerical simulations of hyporheic flow and denitrification throughout the Mississippi River network using a hydrogeomorphic model. We find that vertical exchange with sediments beneath the riverbed in hyporheic zones, driven by submerged bedforms, has denitrification potential that far exceeds lateral hyporheic exchange with sediments alongside river channels, driven by river bars and meandering banks. We propose that geomorphic differences along river corridors can explain why denitrification efficiency varies between basins in the Mississippi River network. Our findings suggest that promoting the development of permeable bedforms at the streambed - and thus vertical hyporheic exchange - would be more effective at enhancing river denitrification in large river basins than promoting lateral exchange through induced channel meandering.