As an important failure form of the turbine blade, creep-fatigue interaction damage affects the safe operation and maintenance strategy of aero-engine, and has been the focus of scientific research and the academic community. Firstly, based on the Kachanov-Rabotnov-Lemaitre continuum damage mechanics theory and the nonlinear symmetry of creep damage and fatigue damage, a creep-fatigue life prediction model is constructed considering the interaction effect in this paper. Then, based on the thermal-fluid–solid multi-physical field coupling numerical simulation of the turbine blade, the equivalent method of creep-fatigue load spectrum was explored according to the equal damage criterion and linear damage rule, and the creep-fatigue interaction test of smooth samples of the blade material was conducted to analyze the creep-fatigue fracture morphology. Finally, the stress term in the creep-fatigue life prediction model of blade material is modified by the correction factor α, and the modified creep-fatigue life prediction model of the turbine blade is constructed considering the interaction effect. The results show that the modified creep-fatigue life prediction model considering the interaction effect has a high life prediction ability with an error of 3.9%. The above research has important scientific research value for the life extension design of turbine blades and the improvement of aero-engine maintenance strategy.