The Denitrification-Decomposition (DNDC) model was used to elucidate the role of climate, soil properties, and farming practices in determining spatial and temporal variations in the production and emission of nitrous oxide (N2O) from agriculture in the United States. Sensitivity studies documented possible causes of annual variability in N2O flux for a simulated Iowa corn-growing soil. The 37 scenarios tested indicated that soil tillage and nitrate pollution in rainfall may be especially significant anthropogenic factors which have increased N2O emissions from soils in the United States. Feedbacks to climate change and biogeochemical manipulation of agricultural soil reflect complex interactions between the nitrogen and carbon cycles. A 20% increase in annual average temperature in °C produced a 33% increase in N2O emissions. Manure applications to Iowa corn crops enhanced carbon storage in soils, but also increased N2O emissions. A DNDC simulation of annual N2O emissions from all crop and pasture lands in the United States indicated that the value lies in the range 0.9–1.2 TgN. Soil tillage and fertilizer use were the most important farming practices contributing to enhanced N2O emissions at the national scale. Soil organic matter and climate variables were the primary determinants of spatial variability in N2O emissions. Our results suggest that the United States Government, and possibly the Intergovernmental Panel on Climatic Change (IPCC), have underestimated the importance of agriculture as a national and global source of atmospheric N2O. The coupled nature of the nitrogen and carbon cycles in soils results in complex feedbacks which complicate the formulation of strategies to reduce the global warming potential of greenhouse gas emissions from agriculture.