Finite element model of waist mounting bracket of MD-1200YJ palletizing robot was established, and the accuracy of the finite element model was verified by modal analysis, the modal test, and static analysis. Taking dynamic factors into account, based on the quintic non-uniform, the rational B-splines motion law was carried out, and the analysis showed that this part had the potential of lightweight design. The mass, the maximal stress, and the maximal deformation were minimized as the optimization objectives were determined. The structure parameters as design variables, the first and second natural frequency no reducing and boundary conditions of design variables as the constraint conditions, the approximation models of objective functions and constraint functions were established by the Box-Behnken and the RSM, and the accuracy of these models were verified. The multi-objective optimization mathematical model was established by the methods mentioned above. The optimal solution was obtained by using NSGA-II algorithm, and the optimized model of waist mounting bracket was also gained. The contrastive analysis results between optimized model and initial model showed that the mass reduction was 8.2%, as the first two natural frequencies were increased, bounding with the maximum stress and deformation within allowable values range. The validity of this optimization design method was verified.