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• Sobol' method is used to evaluate the sensitivity of APSIM-Wheat yield predictions. • Yield is most sensitive to initial nitrogen amount, soil parameters, precipitation. • Estimated yield is influenced most by the limiting resource under given conditions. • Scenarios for high fertilization level or dry seasons have lower yield variability. The performance of cropping system models is often limited by uncertainties in model parameters and inputs. This study aims to explore how model yield prediction responds to these uncertainties under various environmental and management conditions. The Sobol' method was used to investigate the sensitivity of the Agricultural Production Systems SIMulator (APSIM)-Wheat yield prediction to the following factors: air temperature (maximum and minimum), precipitation, initial soil nitrogen content, nitrogen fertilization amount, and soil hydraulic parameters. Eighteen scenarios were defined to consider a combination of three weather conditions (wet, normal, and dry growing season, based on the historical climatology of the Wimmera district of Victoria, Australia), three soil types (sandy, loamy, and clayey soils), and two nitrogen fertilization applications (50 and 100 kg N/ha). Eight thousand APSIM simulations were used to calculate the first order and total sensitivity indices for each scenario. The effects of weather, soil water characteristics and nitrogen availability were estimated by measuring their impacts on sensitivity indices. Our results show that yield was more sensitive either to variables that control water availability (precipitation and soil type) or variables that control nitrogen availability, depending on which was more limiting to wheat growth under the scenario. For example, in case of low nitrogen fertilization scenario, the initial nitrogen content sensitivity ranked first. Variation of this factor contributed 64% to 79% to the variance in simulated yield for clayey soils, nearly four times higher than the second-ranked factor (nitrogen fertilization amount). Soil hydraulic parameters and precipitation were most important when the crop growth was more constrained by water availability than by nitrogen availability. In the case of sandy soils in dry years with high nitrogen fertilization level, soil parameters and precipitation accounted for 83% of the yield variability. Minimum temperature consistently ranked as the least important factor under all scenarios. This work will help researchers better understand the model inputs' impacts on the simulated yield variability under various soil, management, and weather conditions. The results also support agronomists and practitioners in the optimal use of the APSIM-Wheat model as a management tool. [Display omitted] [ABSTRACT FROM AUTHOR]