In this study, a three-factor, three-level Box-Behnken design with response surface methodology and quadratic programming were used to maximize the total organic carbon (TOC) removal and minimize the H2O2 residual in the effluent of the combined UV-C/H2O2/VUV system for the treatment of actual slaughterhouse wastewater. The initial TOC concentration (TOCo), the initial concentration of H2O2, and the irradiation time were the three independent variables studied in the design of experiments. The multiple response approach was used to obtain desirability response surfaces at the optimum factor settings. Thus, the optimum conditions to achieve a maximum TOC removal of 46.19% and a minimum H2O2 residual of 1.05% were TOCo of 213 mg/L, H2O2,o of 450 mg/L, and irradiation time of 9 min. The obtained optimal operating conditions were validated with an additional test. Consequently, maximum TOC removal of 45.68% and minimum H2O2 residual of 1.03% were obtained experimentally, confirming the reliability of the statistical model.