Nitrate is one of the most widespread and persistent pollutants in our time. Our understanding of nitrate dynamics has advanced substantially in the past decades, although its predominant drivers across gradients of climate, land use, and geology have remained elusive. Here we collated nitrate data from 2061 rivers along with 32 watershed characteristic indexes and developed machine learning models to reconstruct long-term mean (multi-year average) nitrate concentrations in the contiguous United States (CONUS). The trained models show similarly satisfactory model performance and can predict nitrate concentrations in chemically-ungauged places with about 70% accuracy. Further analysis revealed that five (out of 32) indexes (drivers) can explain about 70% of spatial variations in mean nitrate concentrations. The five influential drivers are nitrogen application rates Nrate and urban area Aurban% (human drivers), mean annual precipitation and temperature (climate drivers), and sand percent Sand% (soil property driver). Nitrate concentrations in undeveloped sites are primarily modulated by climate and soil property; they decrease with increasing mean discharge and Sand%. Nitrate concentrations in agriculture and urban sites increase with Nrate and Aurban% until reaching their apparent maxima around 10,000 kg/km2/yr and around 25%, respectively. Results indicate that nitrate concentrations may remain similar or increase with growing human population. In addition, nitrate concentrations can increase even without human input, as warming escalates water demand and reduces mean discharge in many places. These results allude to a conceptual model that highlights the impacts of distinct drivers: while human drivers predominate nitrogen input to land and rivers, climate drivers and soil properties modulate its transport and transformation, the balance of which determine long-term mean concentrations. Such mechanism-based insights and forecasting capabilities are essential for water management as we expect changing climate and growing agriculture and urbanization.