This paper deals with finding optimum reaction conditions for wet air oxidation (WAO) of malathion aqueous solution, by Response Surface Methodology. Reaction conditions, which affect the removal efficiencies most during the non-catalytic WAO system, are: temperature (60-120 °C), applied pressure (20-40 bar), the pH value (3-7), and reaction time (0-120 min). Those were chosen as independent parameters of the model. The interactions between parameters were evaluated by Box-Behnken and the quadratic model fitted very well with the experimental data (29 runs). A higher value of R2 and adjusted R2 (>0.91) demonstrated that the model could explain the results successfully. As a result, optimum removal efficiency (97.8%) was obtained at pH 5, 20 bars of pressure, 116 °C, and 96 min. These results showed that Box-Behnken is a suitable design to optimize operating conditions and removal efficiency for non-catalytic WAO process. The EC20 value of raw wastewater was measured as 35.40% for malathion (20 mg/L). After the treatment, no toxicity was observed at the optimum reaction conditions. The results show that the WAO is an efficient treatment system for malathion degradation and has the ability of converting malathion to the non-toxic forms.