Sugarcane production relies on the application of large amounts of nitrogen (N) fertilizer. However, application of N in excess of crop needs can lead to loss of N to the environment, which can negatively impact ecosystems. This is of particular concern in Australia where the majority of sugarcane is grown within catchments that drain directly into the World Heritage listed Great Barrier Reef Marine Park. Multiple factors that impact crop yield and N inputs of sugarcane production systems can affect N use efficiency (NUE), yet the efficacy many of these factors have not been examined in detail. We undertook an extensive simulation analysis of NUE in Australian sugarcane production systems to investigate (1) the impacts of climate on factors determining NUE, (2) the range and drivers of NUE, and (3) regional variation in sugarcane N requirements. We found that the interactions between climate, soils and management produced a wide range of simulated NUE, ranging from ~0.3 Mg cane (kg N)-1, where yields were low (i.e. 5 Mg cane (kg N)-1 in plant crops where yields were high and N inputs low. Of the management practices simulated (N fertilizer rate, timing and splitting; fallow management; tillage intensity; and in-field traffic management), the only practice that significantly influenced NUE in ratoon crops was N fertilizer application rate. N rate also influenced NUE in plant crops together with the management of the preceding fallow. In addition, there is regional variation in N fertilizer requirement that could make N fertilizer recommendations more specific. While our results show that complex interrelationships exist between climate, crop growth, N fertilizer rates and N losses to the environment, they highlight the priority that should be placed on optimizing N application rate and fallow management to improve NUE in Australian sugarcane production systems. New initiatives in seasonal climate forecasting, decisions support systems and enhanced efficiency fertilizers have potential for making N fertilizer management more site specific, an action that should facilitate increased NUE.