For accurately demonstrating the crack growth behavior and the representing the damage accumulation process, a novel creep-fatigue interaction damage model was proposed. In this model, the maximum stress of the cyclic loading was introduced into the fatigue damage model, which well denoted the crack growth behavior of the low cycle fatigue. What’s more, the mutual effect between creep and fatigue was also considered in this model using a non-linear summation approach. Furthermore, the crack growth behavior in creep-fatigue regime was conducted using a novel microstructural modeling approach, where the microstructure was generated using the Voronoi tessellation method. The intergranular fracture of the creep mechanism and the transgranular failure of the fatigue/creep-fatigue mechanism were all demonstrated by the microstructural modeling simulations. The failure type in creep-fatigue mechanism was related to the duration time of the peak load. The effect of the grain size, the grain uniformity and the grain boundary on creep, fatigue and creep-fatigue crack growth behavior was revealed, where the damage evolution process was provided.