The CuO@Al2O3 (EPC) (prepared by an electroless plating and calcining method) was used to activate peroxymonosulfate (PMS) for advanced oxidation of sulfamethoxazole (SMX) in deionized water, and effects of three key parameters of its all parameters (i.e., CuO@Al2O3 (EPC) dosage, PMS dosage, and initial solution pH) on the CuO@Al2O3 (EPC)/PMS system were studied. Under the optimal conditions (i.e., [catalyst](0) = 0.5 g/L, [PMS](0) = 0.4mM and initial solution pH of 6.2), the SMX removal efficiency obtained by the CuO@ Al2O3 (EPC)/PMS process was 99%, while the SMX removal efficiency were 76% and 72% in CuO@ Al2O3 (IC) (prepared by an impregnation-calcination method)/PMS and CuO/PMS system respectively. Adding H2PO4- into CuO@Al2O3 (EPC)/PMS system decreased the SMX removal efficiency, while the degradation efficiency was improved when Cl- was introduced the oxidation system. Furthermore, five possible degradation pathways of SMX were proposed according to the analysis results of intermediates detected by UPLC-QTOF-MS/MS. The biological toxicities of the degraded SMX solution were evaluated by activated sludge inhibition experiments. What is more, it was found that three radicals (i.e. SO4 center dot-, (OH)-O-center dot and O-2(center dot-)) made contributions to SMX degradation in the CuO@Al2O3 (EPC)/PMS system according to radicals scavenging experiments. Residual PMS, and generated SO4 center dot- and (OH)-O-center dot radicals were quantified in CuO@Al2O3 (EPC)/PMS system, and the electron paramagnetic resonance (EPR) was used to detect the generation of radicals. Finally, the mechanism of the CuO@Al2O3 (EPC)/PMS system was proposed according to analysis data of XPS and radical scavenging experiments.