In order to solve the problems of poor reliability and low precision in the installation operation of steel pipe pile foundation of deep-sea wind turbine generator pile foundation at a depth of 45.000 m, the structure optimization of a new guide frame for the installation of steel pipe pile foundation of deep-sea wind turbine generator is performed. Combined Finite Element Method (FEM) with tests, the comprehensive research on the guide frame is conducted in environmental parameter and applied load, structure form, operation condition, and structure strength and structure stability. The sea trial proves that the precision and efficiency of pile driving of optimized guide frame meet the requirements of technical indicators, and can greatly improve the speed and quality in installation operation of steel pipe pile foundation of deep-sea wind turbine generator.