Aiming at the problem of lacking of green treatment technologies for pharmaceutical wastes, the current study was carried out to investigate the detoxification effect of base-catalyzed hydrothermal oxidation on diclofenac sodium (DS) medicine. The corresponding operation method was established and the reaction parameters were optimized. The suitable experimental levels were determined by single-factor design, and response surface methodology (RSM) was carried out to further establish the optimum conditions under multi-factor interaction. The results showed that base-catalyzed hydrothermal oxidation was an efficient approach for the detoxification of DS by dechlorination. The optimal parameters were, H₂O₂: DS 0.3mL/mg, reaction time 98min, reaction temperature 196℃, respectively. It was noted that the determined value was 98.9% and the predicted value was 99.6% with a relative error of 0.70%. Determination and analysis of the degradation products showed that there were two different reaction pathways for the degradation of DS by base-catalyzed hydrothermal oxidation: (1) the C-N bond between the two benzene rings cleaved, followed by benzene rings opened and dechlorinated through oxidation; (2) the benzene rings directly hydroxylated, followed by benzene rings opened and dechlorinated through oxidation. This study provides a green and environmentally benign approach for the detoxification of waste DS medicine.