Besides the solid free-form fabrication technology, milling operation is an alternative applicable method to make complex cooling channels conform to the surface of the mold cavity. This paper presents the U-shape milled groove conformal cooling channels and proposes the design optimization process in order to obtain an optimal cooling channels' configuration and target mold temperature. The relation between the cycle averaged thermal behavior of the mold cavity and the two-dimensional configuration of cooling channels was first investigated thoroughly by an analytical method. Design of experiment and 2D simulation were done to obtain the mold wall temperature and to check the feasibility of the analytical method. The optimization process of the free-form conformal cooling channels is based on the combination of both analytical method and 3D CAE simulation. The analytical step relies on explicit mathematic formulas, so it can approach the neighboring optimal solution quickly. Subsequently, the three-dimensional heat transfer simulation is applied to fine-tune the optimization results. A case study for a plastic car fender was investigated to verify the feasibility of the proposed method. The results show that conformal cooling channel gives a uniform cooling, reducing the cooling time and increasing the molded part's quality with less effort of plastic designers and high computational efficiency.