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This study is aimed at designing the optimal injection system parameters of common rail diesel engine based on the experiment design theory and the response surface approximate model. First, the spray and combustion simulation model in the FIRE are validated and collated, and the relationship between the parameter C2 of the KH-RT model and nozzle configuration was concluded, enhancing the simulation precision of the model. Then, the central composite method is used to design the experimental matrix for the parameters and the software FIRE is used to calculate. The economic-based comprehensive objective function is established using the response surface approximation technique. The approximate model is optimized, combining global optimization and local optimization methods together and the optimum combination of the parameters of the injection system is obtained, which reduced preferable the work of the parameters design of the common rail diesel engine injection system.