Performance modeling of wastewater treatment systems has now become an attractive area of investigation for the design, analysis, and optimization of operations. Mathematical modeling of membrane bioreactor (MBR) treatment is a powerful tool for predicting effluent quality. In this study, a bioreactor coupled with a membrane filtration process (MBR) was employed to treat municipal wastewater. An experimental design based on the response surface methodology (RSM) was applied to investigate the effects of operating conditions, such as hydraulic retention time (HRT), aeration rate (AR), and transmembrane pressure (TMP), on the removal efficiencies of chemical oxygen demand (COD), total suspended solids (TSS), and total nitrogen (TN). The results demonstrated a strong agreement between experimental data and model predictions. Furthermore, the RSM results display the effects of the operating parameters and their interactive effects on pollution removal. The maximum removal efficiency was achieved, exhibiting 95% of COD, 99.7% of TSS, and 93% of TN. These findings provide the effective use of statistical modeling to enhance MBR process performance, achieving sustainable and energy-efficient conditions.