Abstract: This study aim to realize the enhanced removal of nitrogen and phosphorus in the treatment of low C/N ratio domestic sewage, by optimizing the key operation conditions of an integrated process of the multi-stage A/O (anoxic/oxic) + BAF (biological aerated filter). Single factor experiments were conducted to study the effects of HRT (hydraulic retention time), three-point inlet water ratio and BAF packing height on the removal of maior pollutants in the system, furthermore, by BBD second-order mode center review to design multi-factor experiment. The response surface methodology was used to analyze the interactive influence of the above three factors on TN (total nitrogen) and TP (total phosphorus) removal, so as to obtain the optimal operation conditions of the system and the predicted removal rates of the model, based on those conditions, run a parallel experiment to verify the relative error between the actual value of TN and TP removal rate and the predicted value. The results showed that: (1) In the single factor experiment, the conditions for the optimum removal effect of main pollutants in the system were HRT 9 h, inlet water ratio 5:3:2 and packing height 1800 mm. (2) By analyzing the response surface, it is indicated that the three factors have significant interaction influence on the removal of TN and TP. According to the regression equation fitted by the model, the optimal operating conditions were: HRT 8.5 h, inlet water ratio 5:3:2, and packing height 1600 mm, and the predicted removal rates of TN and TP were 84.88% and 94.37%. (3) The results of verification show that the average concentrations of TN and TP in influent were 68.8 and 5.4 mg/L, and in effluent were 10.61 and 0.32 mg/L, respectively, and the corresponding actual removal rates were 84.15% and 94.01%, respectively. Comparing the actual values with the predicted values of TN and TP removal rates, the relative errors were only 0.86% and 0.38%. The research shows that the application of the response surface methodology to model and optimize the multi-stage A/O+BAF process of domestic sewage treatment was reliable and enhanced removal of nitrogen and phosphorus.