National-level summaries of crop production and nutrient use efficiency, important for international comparisons, only partially elucidate agricultural dynamics within a country. Agricultural production and associated environmental impacts in large countries vary significantly because of regional differences in crops, climate, resource use and production practices. Here, we review patterns of regional crop production, nitrogen use efficiency (NUE), and major inputs of nitrogen to US crops over 1987-2012, based on the Farm Resource Regions developed by the Economic Research Service (USDA-ERS). Across the US, NUE generally decreased over time over the period studied, mainly due to increased use in mineral N fertilizer above crop N requirements. The Heartland region dominates production of major crops and thus tends to drive national patterns, showing linear response of crop production to nitrogen inputs broadly consistent with an earlier analysis of global patterns of country-scale data by Lassaletta et al. (2014). Most other regions show similar responses, but the Eastern Uplands region shows a negative response to nitrogen inputs, and the Southern Seaboard shows no significant relationship. The regional differences appear as two branches in the response of aggregate production to N inputs on a cropland area basis, but not on a total area basis, suggesting that the type of scaling used is critical under changing cropland area. Nitrogen use efficiency (NUE) is positively associated with fertilizer as a percentage of N inputs in four regions, and all regions considered together. NUE is positively associated with crop N fixation in all regions except Northern Great Plains. It is negatively associated with manure (livestock excretion); in the US, manure is still treated largely as a waste to be managed rather than a nutrient resource. This significant regional variation in patterns of crop production and NUE vs N inputs, has implications for environmental quality and food security.