Commercial nanosized zero-valent copper (nZVC) was used as persulfate (PS) activator in combination with ultrasonic irradiation (US) for the oxidative degradation of typical antibiotic sulfamethazine (SMZ) in this study. Compared with other processes, the combined nZVC-PS-US process significantly enhanced SMZ removal due to a synergistic interaction between sonolysis and a heterogeneous reaction. Almost complete SMZ removal was achieved within 60 min using a PS dose of 0.5 mM and a nZVC concentration of 64 mg/L at pH 3.06, with US at 0.4 W/mL and 40 kHz. The presence of NO3–, SO42−, HCO3–, Cl− and humic acid demonstrated adverse effects on SMZ degradation. Moreover, the inhibitory effect of different inorganic anions on SMZ degradation followed the sequence of HCO3– > SO42−> NO3– > Cl− > no salt. Electron spin resonance and radical scavenging tests indicate that the primary reactive species was SO4•−, while •OH played a less important role. Cu+ is an active copper species in activating PS. The production of Cu+ and Cu2+ induced by Cu0 and US favored the continuous decomposition of PS as well as the production of SO4•− at the surface of nZVC. Nine intermediates were identified and four oxidation pathways were proposed, the aniline moiety oxidation, SO2 extrusion/smile-type rearrangement and S-N bond cleavage were the major pathways. Practicality and effectiveness of nZVC-PS-US was confirmed when other organic micro-pollutants and SMZ added to raw waters were tested. The findings reported here offer promising implications in developing the utilization of nZVC in advanced oxidation for treatment of wastewater.