The present study aims to increase the selectivity of C2H2 in the partial oxidation process of methane, employing design of experiments (DOE) and computational fluid dynamics (CFD). Central composite design is used to design tests, and analysis of variance is performed to evaluate the percentage of contribution of operating factors on system performance. The operating factors considered in the analysis are preheating temperature, O-2/CH4 ratio, and inlet velocity. The system responses are selectivity of C2H2 and conversion of CH4. Furthermore, an optimization method using response surface methodology is utilized to determine the optimal values of operating factors that lead to the best system performance. The findings indicate that increasing the preheating temperature and O-2/CH4 ratio boosts the selectivity of C2H2 and reduces the methane conversion percentage, while increasing the inlet velocity has the opposite effect. The optimization method indicates that the maximum selectivity of C2H2 is achieved with conversion of CH4 of 95% under optimal conditions, namely preheating temperature of 1151.13 K, inlet velocity of 222.8 m/s, and O-2/CH4 ratio of 0.59.