A systematic approach is proposed to find optimal operational conditions for nitrogen and phosphorus (N, P) removal in a biological nutrient removal process. The approach is a dual optimization strategy using modeling, variable selection, design of experiments, and optimization with multiple response surface methodology. The study focused on determining interactive effects between independent variables for N and P removal, which were selected through a new sensitivity analysis considering the effluent quality index. After selecting key operational variables, a multiple response surface model based on a new desirability function was used for the dual optimization of both N and P removal. The proposed method was applied to a standard A(2)O process and obtained the optimized removal efficiencies of 78.0% and 80.0% for N and P, respectively. This study confirmed that the proposed dual optimization method was useful to systematically optimize N and P removal in a biological nutrient removal process and also can be applied to any other biological processes.