This dataset consists of input and output datasets for estimating nitrogen (N) and phosphorus (P) balances for the Mississippi River Basin from 1950 to 2017. The N balance was calculated as the difference between inputs (fertilizer, manure, wastewater treatment facility effluent, N fixation, and atmospheric deposition) and outputs (crop uptake and removal in harvest and gaseous emissions to the atmosphere). The P balance was calculated as the difference between inputs (fertilizer, manure, wastewater treatment facility effluent, and weathering) minus outputs (specifically, P harvested and removed in crops, hay, and pasture).