The purpose of this study was to apply the experimental Box–Behnken design (BBD) to evaluate the effect and, therefore, the optimal values of three chosen factors on the efficiency of the UV/H2O2 process to decolorize Ponceau S (PS) aqueous solutions. The factors studied at three levels were the irradiated volume of dye solution, the dye solution turbidity and the H2O2 dosage. The equations generated, analysis of variance (ANOVA), contour plots and response surface plots were used to analyze the relationship between independent variables and the outcomes of experiments. The fitted model was significant, with an adjusted coefficient of determination (adj-R2 = 0.9835). The results showed that factors such as H2O2 dosage and irradiated volume were the main parameters that affected the decolorization efficiency of the PS aqueous solution, while the turbidity had a slight effect on the response. In addition, significant values were obtained for irradiated volume and H2O2 dosage interaction and square terms of all studied factors. Furthermore, the optimal conditions for decolorization of the PS aqueous solution were found to be an irradiated volume of 257.59 mL, a turbidity of 13 NTU and an H2O2 dosage of 1.76 mM.