Abstract Conservation tillage has been promoted as an effective practice to preserve soil health and enhance agroecosystem services. Changes in tillage intensity have a profound impact on soil nitrogen cycling, yet their influence on nitrate losses at large spatiotemporal scales remains uncertain. This study examined the effects of tillage intensity on soil nitrate losses in the US Midwest from 1979–2018 using field data synthesis and process-based agroecosystem modeling approaches. Our results revealed that no-tillage (NT) or reduced tillage intensity (RTI) decreased nitrate runoff but increased nitrate leaching compared to conventional tillage. These trade-offs were largely caused by altered water fluxes, which elevated total nitrate losses. The structural equation model suggested that precipitation had more pronounced effects on nitrate leaching and runoff than soil properties (i.e. texture, pH, and bulk density). Reduction in nitrate runoff under NT or RTI was negatively correlated with precipitation, and the increased nitrate leaching was positively associated with soil bulk density. We further explored the combined effects of NT or RTI and winter cover crops and found that incorporating winter cover crops into NT systems effectively reduced nitrate runoff but did not significantly affect nitrate leaching. Our findings underscore the precautions of implementing NT or RTI to promote sustainable agriculture under changing climate conditions. This study provides valuable insights into the complex relationship between tillage intensity and nitrate loss pathways, contributing to informed decision-making in climate-smart agriculture.