Nano-particles have been successfully and widely applied in many industrial applications. The wet-type mechanical milling process is a popular method used to produce nano-particles. Therefore, it is very important to improve milling process capability and quality by setting the optimal milling parameters. In this research, the parameter design of the Taguchi method, response surface method (RSM) and genetic algorithm (GA) are integrated and applied to set the optimal parameters for a nano-particle milling process. The orthogonal array experiment is conducted to economically obtain the response measurements. Analysis of variance (ANOVA) and main effect plot are used to determine the significant parameters and set the optimal level for each parameter. The RSM is then used to build the relationship between the input parameters and output responses, and used as the fitness function to measure the fitness value of the GA approach. Finally, GA is applied to find the optimal parameters for a nano-particle milling process. The experimental results show that the integrated approach does indeed find the optimal parameters that result in very good output responses in the nano-particle wet milling process.