Considering the relationship between inhomogeneous plastic deformation and fatigue damage, deformation inhomogeneity evolution and fatigue failure of superalloy GH4169 under temperature 500 °C and macro tension compression cyclic loading are studied, by using crystal plasticity calculation associated with polycrystalline representative Voronoi volume element (RVE). Different statistical standard deviation and differential entropy of meso strain are used to measure the inhomogeneity of deformation, and the relationship between the inhomogeneity and strain cycle is explored by cyclic numerical simulation. It is found from the research that the standard deviations of each component of the strain tensor at the cyclic peak increase monotonically with the cyclic loading, and they are similar to each other. The differential entropy of each component of the strain tensor also increases with the number of cycles, and the law is similar. On this basis, the critical values determined by statistical standard deviations of the strain components and the equivalent strain, and that by differential entropy of strain components, are, respectively, used as fatigue criteria, then predict the fatigue–life curves of the material. The predictions are verified with reference to the measured results, and their deviations are proved to be in a reasonable range.