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A method combining crystal plasticity (CP), the eXtended Finite Element Method (XFEM), and cohesive zone model (CZM) with traction separation law is developed for an Al-Cu-Mg alloy to predict the effect of grain orientation on fatigue crack propagation (FCP) during stage ΙΙ within a single crystal. The simulation results show that of all the orientations, Goss grain possesses the largest fatigue crack deflection, then followed by Cube orientation. Comparatively, Brass, Copper, S and Random grains have relatively small crack deflection angles. Besides, it is found that Goss grain with the largest fatigue crack deflection possesses the lowest FCP rate as compared with other orientations. The results of simulations are consistent with previous experimental observations. This indicates that this coupled CP XFEM CZM simulation method is capable of well predicting the effect of grain orientation on FCP during fatigue stage ΙΙ of Al-Cu-Mg single crystal.