In a flexible multi-body dynamic system the typical topological optimization method for structures cannot be directly applied, as the stiffness varies with position. In this paper, the topological optimization of the flexible multi-body dynamic system is converted into structural optimization using the equivalent static load method. First, the actual boundary conditions of the control system and the approximate stiffness curve of the mechanism are obtained from a flexible multi-body dynamical simulation. Second, the finite element models are built using the absolute nodal coordination for different positions according to the stiffness curve. For efficiency, the static reanalysis method is utilized to solve these finite element equilibrium equations. Specifically, the finite element equilibrium equations of key points in the stiffness curve are fully solved as the initial solution, and the following equilibrium equations are solved using a reanalysis method with an error controlled epsilon algorithm. In order to identify the efficiency of the elements, a non-dimensional measurement is introduced. Finally, an improved evolutional structural optimization (ESO) method is used to solve the optimization problem. The presented method is applied to the optimal design of a die bonder. The numerical results show that the presented method is practical and efficient when optimizing the design of the mechanism.