Abstract: Clamping is the essential process for manufacturing. The reasonable design of is a crucial factor for enterprise in terms of either the workpiece quality and machining accuracy, or safety and efficiency of production. Therefore, this chapter is aimed at to optimize the design of clamping layout by use of the multi-method fusion based on orthogonal design. Firstly, to establish the clamping stability mathematical model to judge whether the workpiece is stable or not. Secondly, to execute model establishment and use ANSYS and genetic algorithm interface operation by means of ANSYS. Then, the orthogonal experimental design method is adopted on this chapter to select better genetic algorithm parameters. Finally, the shell thin-walled parts are taken as an example to conduct the test, and smaller clamping deformation and more reasonable clamping layout are obtained, the machining accuracy and quality of the workpiece are heightened.