The efficiency of Fenton oxidation was inhibited by the high content of salt in the industrial wastewater. However, enhanced mineralization of hypersaline industrial wastewater is necessary for advanced treatment and subsequent wastewater salt recovery process. Therefore, Fe2+ and Cu2+ catalyzed UV-Fenton oxidation were carried out to improve the total organic carbon (TOC) removal efficiency for a hypersaline wastewater from resin manufacturing. The performance of UV-Fe/Cu-Fenton oxidation was comparatively investigated and optimized using response surface methodology (RSM) to develop a practical high-efficient mineralization treatment technique for hypersaline wastewater. More than 90% of TOC was removed under optimal conditions of UV-Fe2+ and UV-Cu2+-Fenton oxidation, namely 9.6 mM Fe2+ and 176 mM H2O2, and 2.95 mM Cu2+ and 276 mM H2O2, respectively. The reactive oxygen radicals identified using electron spin resonance (ESR) spectroscopy revealed that hydroxyl radical was dominant oxidant in UV-Fe2+-Fenton process, while HO2·/O2·− played a more important role in the UV-Cu-Fenton system. The Cl− effect is also different for UV Fe and Cu Fenton. Moreover, no scaling and sludge problem makes UV-Cu-Fenton a promising alternative method for efficient mineralization of hypersaline industrial wastewater.