An optimization procedure to decide layouts and shapes of cooling channels in a plastic injection molding die is presented for a reduction of molded defects in a plastic product. To confirm the validity, the proposed method is applied to the design problems given by different thermal and geometrical conditions. In the proposed method, the design problem of cooling channels, which is the most effective factor to control temperature distribution in the die, is formulated as the multi-objective optimization problem adopted two objective functions. One is to evaluate the temperature distribution in the die for reduction of some defects such as residual stresses, and the other is to measure the cooling rate of injected plastic to improve productivity. To calculate these functions, the transient cooling process of the plastic injection molding is simulated numerically. The design variables are the cooling channel arrangements which represent a complex cooling pipe. The design space is approximated by a response surface based on the design of experiment, which is applied to decide combinations of the design variables, to optimize efficiently under required reliability. An optimum layout of cooling channels is decided by optimizing the response surface.