Summary: Cooling system design is of great importance for plastic injection molding because it significantly affects the productivity and quality of the final products. In this paper, a systematic computer-aided approach is developed to achieve the cooling system optimal design. This approach expiates the trial and error process normally practiced in conventional cooling system design based on the designer’s experience and intuition. Various aspects of the optimization process for cooling system design are investigated including cooling analysis using boundary element method (BEM), a perturbation-based approach to design sensitivity analysis, optimization problem formulation, and a novel hybrid optimizer based on Davidon-Fletcher-Powell (DFP) method and simulated annealing (SA). A case study shows that the proposed methodology for cooling system optimal design is efficient, robust and practical.