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Human activities have caused considerable perturbations of the nitrogen (N) cycle, leading to a ~20% increase in the concentration of atmospheric nitrous oxide (N2O) since the preindustrial era. While substantial efforts have been made to quantify global and regional N2O emissions from cropland, there is large uncertainty regarding how climate change and variability have altered net N2O fluxes at annual and decadal time scales. Herein, we applied a process‐based dynamic land ecosystem model (DLEM) to estimate global N2O emissions from cropland driven by synthetic N fertilizer application and multiple environmental factors (i.e., elevated CO2, atmospheric N deposition, and climate change). We estimate that global cropland N2O emissions increased by 180% (from 1.1 ± 0.2 to 3.3 ± 0.1 Tg N year−1; mean ±1 standard deviation) during 1961–2014. Synthetic N fertilizer applications accounted for ~70% of total emissions during 2000–2014. At the regional scale, Europe and North America were two leading regions for N2O emissions in the 1960s. However, East Asia became the largest emitter after the 1990s. Compared with estimates based on linear and nonlinear emission factors, our results were 150% and 186% larger, respectively, at the global scale during 2000–2014. Our higher estimates of N2O emissions could be attributable to the legacy effect from previous N addition to cropland as well as the interactive effect of N addition and climate change. To reduce future cropland N2O emissions, effective mitigation strategies should be implemented in regions that have received high levels of N fertilizer and regions that would be more vulnerable to future climate change. Key Points: Synthetic N fertilizer contributed to N2O emissions of 2.0 ± 0.1 Tg N year−1 from global cropland between 2000 and 2014Uncertainty remains in fertilizer‐induced N2O emissions due to temporal and spatial differences in current N fertilizer data setsChanges in environmental factors increased cropland N2O emissions; however, the magnitude of environmental effects remain highly uncertain [ABSTRACT FROM AUTHOR]