The optimization and mechanism for oxidation of the waste anion exchange resin from the nuclear industry in supercritical water were investigated. To achieve the maximum chemical oxygen demand (COD) and total nitrogen (TN) removal efficiencies, the response surface methodology (RSM) was employed to optimize four operating variables. Two quadratic polynomial models with satisfactory accuracy were established based on the experimental results. Under optimized conditions, the removal rates of the COD and TN could reach 99.91 and 36.02%, respectively. According to the identification of intermediates under different reaction conditions, a detailed degradation mechanism involving Huffman decomposition, depolymerization, oxidation, ring-opening, recombination, and finally oxidation to small molecules was proposed. As the quaternary ammonium falls off, the reaction mainly follows two routes. Phenols and amides were the main intermediates. The optimization and mechanism analysis would provide the theoretical basis and guidelines for the applications of supercritical water oxidation technology in the minimization and inorganic stabilization of radioactive waste.