This study presents the innovative optimization design procedure to increase the strength and fatigue safety of a fastening system under the static and fatigue loading. Applying the uniform design of experiment, a group of simulation experiment is generated. Utilizing ANSYS/Workbench software, the finite element models are constructed and used to evaluate the von Mises stress of rail clip for EN 13146-1 and EN 13146-2 testing simulations. Furthermore, the fatigue safety factor of rail clip for EN 13146-4 testing simulation is also presented. By the Kriging interpolation method, the surrogate models are rebuilt by the input and output data from the uniform design. Applying grey relational analysis, entropy weighting method, genetic algorithm and Hooke–Jeeves algorithm, the improvement design version is presented by solving the multi-objective optimization problem. Compared with the original design, the maximum von Mises stress of rail clip has been decreased to 25.189 MPa, the fatigue safety factor is upgraded to 3.829. As a result, the strength and fatigue safety of the rail clip in the fastening system is increased.