Background & Aims of the Study: Diethyl phthalate (DEP) cannot be proficiently degraded by ultraviolet (UV) radiation and hydrogen peroxide (H2O2) oxidation separately; however, the photo-Fenton method is verified to be operative and can completely degrade this pollutant. Currently, advanced oxidation methods have been growing to be employed for the remediation of industrial wastewater. In the present study, the photo-Fenton process investigated the degradation and mineralization of the aqueous solution containing DEP. Materials and Methods: Synthesized wastewater was used in this study. In addition, the effects of operative factors, such as the initial concentrations of H2O2, ferrous ion, and DEP, have been studied. The response surface methodology and Box-Behnken design of experiments were applied to examine the effects of three sovereign variables on the response functions to obtain the optimum circumstances. Results: The analysis of variance was carried out to determine the importance of the effects of independent variables on the response function. Various amounts of variables were optimized for the removal of DEP. At optimum conditions (i.e., H2O2 concentration of 400 mg/l, ferrous concentration of 75 mg/l, and DEP concentration of 50 mg/l) and 60 min following the reaction, the rates of degradation efficiency for DEP and chemical oxygen demand (COD) were 100% and 85.3%, respectively. Conclusion: According to the obtained results, the suggested quadratic model showed good correctness. The statistical analysis of the model indicated that the model was satisfactory to predict the performance of the processes. The obtained findings demonstrated that the photo-Fenton processes can be used for the complete and partial removal of DEP and COD from wastewater, respectively. The benefits of the photo-Fenton process were less sludge formation, fewer chemicals, and time obligation but at the cost of consumed power. The power consumption can be reduced by employing sunlight instead of artificial UV light to a larger amount. The photo-Fenton procedure was influential in the degradation of DEP and can considerably decrease COD.