Accurate assessment of the creep life of film cooling hole structures is critical for long-life design and safe operation of aero engines and gas turbines. Firstly, through the high temperature creep experiment of nickel-based single crystal superalloy with film cooling hole, the microstructure evolution process under multiaxial stress state around film hole is characterized. Then, considering the directional effect of rafting structure and the influence of multiaxial stress, a fourth-order tensor is used to describe the evolution of γ phase width, and the microstructure evolution model accounting for multi-axial stress states is established. The microstructure evolution is coupled into the crystal plasticity constitutive model by Orowan stress. Meanwhile, based on continuous damage mechanics, a new multiaxial damage evolution law is established by introducing a multiaxial ductility factor into the constitutive model. The improved crystal plasticity constitutive model can effectively predict the microstructural evolution under multiaxial stress conditions. Furthermore, the combination of the modified crystal plasticity constitutive model and the critical distance method considering stress gradients is used for life prediction of film cooling hole structures. The prediction results show the effectiveness and necessity of considering the microstructure evolution in the life prediction.