A central composite rotatable experimental design is used to plan the experiment of laser transmission welding of polymers. Response surface methodology (RSM) is employed to establish the mathematical models of relations between the welding process parameters and the weld strength as well as weld seam width, and then the desirability function coupled with genetic algorithm is used to carry out the multi-objective optimization of the weld strength, weld width and weld cost. It demonstrates that the predicted results of the optimization are in good agreement with the experimental results, so this study provides an effective direction to enhance the weld quality and minimize the weld cost.