Market shortage of high-quality wheat and lack of market competitiveness both exist in wheat production in China. The objective was to evaluate response of CERES-Wheat to different irrigation and nitrogen fertilization managements. Field experiments were conducted in the Guanzhong Plain of Shaanxi Provice during 2014—2016 for two wheat growing seasons. And its relevant outputs were used to estimate grain protein concentration (GPC). The CERES-Wheat was calibrated and evaluated with the experimental data. CERES-Wheat was run with 51years (1966—2016) historical weather data to simulate the GPC and yield, and the optimal irrigation and nitrogen fertilization managements were selected. The CERES-Wheat model could accurately simulate winter wheat growth and GPC under different irrigation and nitrogen fertilization managements. While the aboveground and grain biomass were underestimated with severe nitrogen stress, and the relative root mean square error (RRMSE) values between simulated and measured were 10%~30%, which meant that the simulation results were good or medium. And GPC were overestimated with slight nitrogen stress. The RRMSE of GPC was 3.77%, and the simulation results were still excellent. The CERES-Wheat model was able to be used to simulate winter wheat quality and yield. GPC and yield had different responses to irrigation and nitrogen fertilization. But the coupling effects of irrigation depth and nitrogen fertilization, irrigation depth and irrigation frequency, and irrigation depth and irrigation times could improve GPC and yield at the same time. The selected final optimal management, with a basal dressing of 262.5kg/hm2 and 120mm irrigation depth at wintering stages, showed strong reliability under different climatic conditions in the Guanzhong Plain. The management could simultaneously meet the multiple requirements of high grain quality and yield, and would be more practical.