In order to study the effects of femtosecond laser drilling and electrical discharge machining (EDM) drilling on high cycle fatigue life of nickel based single crystal turbine blade, finite element models for two drilling methods were established respectively. In the process of finite element calculation, combined with the constitutive characteristics of nickel based single crystal and the crystal plastic slip theory, the user defined material mechanical behavior (UMAT) of the single crystal constitutive model was written, and the shear stress distribution on each sliding surface of nickel based single crystal under high cycle fatigue boundary conditions was calculated. Based on the critical plane method, different damage criteria were established for the sliding system and sliding surface under specific stress state. The damage criteria of nickel based single crystal turbine blade suitable for femtosecond laser drilling and EDM drilling were selected, and the high cycle fatigue life prediction models were established respectively. The high cycle fatigue life of single crystal specimen and single crystal turbine blade with two drilling methods were predicted, and compared with the actual high cycle fatigue test results. The comparison error between the calculated life prediction results and the experimental life was about 10%. The research results provide a reference for optimizing the processing technology of aeroengine turbine blades.