Optimizing nitrogen (N) fertilizer management in corn cultivation requires consideration of both yield productivity and environmental sustainability. As one of the most crucial management practices, nitrogen fertilizer rate has been widely studied for its effects on crop yield, soil carbon sequestration, and N loss. However, interactions between N fertilizer application practices (e.g., timing, rates, and additives) and environmental conditions are still not fully understood. Understanding of such complicated interactions is hampered by the challenges of conducting multi-factor control experiments at field scales. In this study, we used an advanced agroecosystem model, ecosys, to evaluate the impacts of different nitrogen application strategies in the U.S. Midwestern agroecosystem. This study aims to answer two major scientific questions: (1) To what extent do environmental conditions and N management practices (e.g. nitrification inhibitors) influence yield and environmental consequences from fall and spring applications? (2) Under what conditions (i.e., environmental and side-dress practices) would side-dress applications outperform spring applications concerning crop production and environmental sustainability? To address these questions using ecosys, we first validated it using extensive N trial data collected across the U.S. Midwest, confirming that ecosys can accurately capture N fertilizer-yield responses and field-scale N cycling measurements (e.g., N leaching and N2O). We then utilized the validated model to simulate the ecosystem water, nitrogen, and carbon dynamics under different N fertilizer application strategies during 2000 to 2021 at the county scale in 12 U.S. Midwestern states. These strategies included combinations of three N application rates (0.75, 1, and 1.33 times of the USDA NASS state-level survey data) and seven N application timings: fall applications with and without nitrification inhibitors; one spring application; and four side-dress applications. For side-dress applications, 25% or 75% of the fertilizer N was applied at planting, with the rest applied at two different times during vegetative growth. This study can provide useful insights to different N fertilizer management practices, and provide guidance for farmers on effectively managing fertilizer in the U.S. Midwest.