The film cooling holes system is an indispensable structure for advanced turbine blades of aircraft engines. The film cooling holes with different slant angles have a significant impact on the service life of the blade. In the work, the effects of film cooling holes with different slant angles on creep rapture behaviors of single crystal Ni-based superalloys were systematically studied by experimental and numerical methods. The creep tests of the samples with different slant film cooling holes were carried out under 260 MPa and 980 °C. The experimental results showed that the creep fracture life first decreases and then increases with the increased slant angle of the film cooling holes. Furthermore, the creep fracture mode, path and mechanism also change significantly, which was related to the difference of stress distribution caused by distinct slant angles of film cooling hole. Based on the stress distribution characteristics obtained by finite element method, the crystal plasticity theory and “skeletal point” method were used to predict the creep life of the flat samples with film cooling holes at different slant angles. The predicted life were in good agreement with the test results.