The frequency and intensity of extreme weather years, characterized by abnormal precipitation and temperature, are increasing. In isolation, these years have disproportionately large effects on environmental N losses. However, multi-year sequences of extreme weather years (e.g., wet-dry vs. dry-wet) and annual crop rotation (legume-cereal vs. cereal-legume) may interact to affect cumulative N losses across the complete crop rotation sequence. We calibrated and validated the DAYCENT model with a comprehensive set of biogeophysical measurements from a maizesoybean rotation managed at three different N fertilizer inputs with and without a winter cereal rye cover crop in Iowa, USA. Our objectives were to determine: i) how two-year sequences of extreme weather years interact with annual crop rotation sequence to affect two-year cumulative N losses, and ii) if the inclusion of a winter cover crop between corn and soybean and N fertilizer management mitigate the effect of extreme weather on N losses. Using historical weather data (1951-2013), we created nine two-year weather scenarios with all possible combinations of the hottest and driest (‘dry’), coolest and wettest (‘wet’), and average (‘normal’) weather years. We analyzed the effects of these scenarios following a period of relatively normal weather. Compared to the normal-normal two-year weather scenario, two-year extreme weather scenarios affected two-year cumulative NO3- leaching (range: -28 to +295%) more than N2O emissions (range: -54 to +21%). Moreover, the two-year weather scenarios had non-additive effects on N losses: although dry weather decreased NO3- leaching in isolation, two-year cumulative NO3- losses from the dry-wet scenario were 89% greater than the normal-normal scenario. Cover crops reduced the effect of extreme weather on NO3- leaching, but not N2O emissions. As the frequency of extreme weather events is expected to increase, understanding of interactions between crop rotation and interannual weather patterns can be used to mitigate the effect of extreme weather on environmental N losses.