The U.S. Midwest, with its intensive agriculture, is a prominent source of nitrous oxide (N2O) but top-down and bottom-up N2O emission estimates differ significantly. We quantify Midwest N2O emissions by combining observations from the Atmospheric Carbon and Transport-America campaign with model simulations to scale the Emissions Database for Global Atmospheric Research (EDGAR). In October 2017 we increased agricultural EDGAR version 4.3.2/5.0 emissions by a factor of 6.3±4.6/3.5±2.7, resulting in Midwest N2O emissions of 0.42±0.28 nmol m-2 s-1. In June/July 2019, a period when extreme flooding was occurring in the Midwest, EDGAR was increased by a factor of 11.4±6.6/9.9±5.7, resulting in N2O emissions of 1.06±0.57 nmol m-2 s-1. Agricultural emissions estimated with the process-based model DayCent (Daily version of the CENTURY ecosystem model) were larger than in EDGAR but still substantially smaller than our estimates. Due to the complexity of N2O emissions, further studies are necessary to fully characterize Midwest emissions.