In this study, lithium (Li) intercalation-induced stress of LiCoO2 with anisotropic properties using three-dimensional (3D) microstructures has been studied systematically. Phase field method was employed to generate LiCoO2 polycrystals with varying grain sizes. Li diffusion and stresses inside the polycrystalline microstructure with different grain size, grain orientation, and grain boundary diffusivity were investigated using finite element method. The results show that the anisotropic mechanical properties and Li concentration-dependent volume expansion coefficient have a very small influence on the Li chemical diffusion coefficients. The low partial molar volume of LiCoO2 leads to this phenomenon. The anisotropic mechanical properties have a large influence on the magnitude of stress generation. Since the Young's modulus of LiCoO2 along the diffusion pathway (a–b axis) is higher than that along c–axis, the Li concentration gradient is larger along the diffusion pathway. Thus, for the same intercalation-induced strain, the stress generation will be higher (∼40%) than that with isotropic mechanical properties as discussed in our previous study (Wu, L., Zhang, Y., Jung, Y.-G., and Zhang, J., 2015, “Three-Dimensional Phase Field Based Finite Element Study on Li Intercalation-Induced Stress in Polycrystalline LiCoO2,” J. Power Sources, 299, pp. 57–65). This work demonstrates the importance to include anisotropic property in the model.