A national V emission high pressure commonrail diesel engine filled with 20% biodieseldiesel blends was optimized by adjusting the 6 injection parameters(Pfin, Tfin, Tint, Qpre, Tinta, Qafter). A multifactor global optimization plan was designed by using hybrid Design of Experiment (DoE). 9 different operating points with different speeds and torques were tested. Less data of the sample sizes were in need for a better accuracy to fit a engine Brake Specific Fuel Consumption (BSFC) model by this method. With the goal of minimum BSFC, the global best combination of injection parameters was calculated with the hybrid optimization algorithm. After the optimization, the BSFC of the biodiesel engine was lessened than before by an average of 2.71%. The hybrid Design of Experiment(DoE) method could cover the shortage of the single factor method of calibration which might cause the local optimum.