The aim of our research was to apply experimental design methodology in the optimization of N, N-Dimethyl-4-nitrosoaniline (RNO, which is indictor of OH radical formation) degradation using gas mixing-circulation plasma process. The reaction was mathematically described as a function of four independent variables [voltage ($X_1$), gas flow rate ($X_2$), liquid flow rate ($X_3$) and time ($X_4$)] being modeled by the use of the central composite design (CCD). RNO removal efficiency was evaluated using a second-order polynomial multiple regression model. Analysis of variance (ANOVA) showed a high coefficient of determination ($R^2$) value of 0.9111, thus ensuring a satisfactory adjustment of the second-order polynomial multiple regression model with the experimental data. The application of response surface methodology (RSM) yielded the following regression equation, which is an empirical relationship between the RNO removal efficiency and independent variables in a coded unit: RNO removal efficiency (%) = $77.71+10.04X_1+10.72X_2+1.78X_3+17.66X_4+5.91X_1X_2+3.64X_2X_3-8.72X_2X_4-7.80X{_1}^2-6.49X{_2}^2-5.67X{_4}^2$. Maximum RNO removal efficiency was predicted and experimentally validated. The optimum voltage, air flow rate, liquid flow rate and time were obtained for the highest desirability at 117.99 V, 4.88 L/min, 6.27 L/min and 24.65 min, respectively. Under optimal value of process parameters, high removal(> 97 %) was obtained for RNO.