Nano-CuFe2O4 has received much attention owing to its application in the heterogeneous activation of peroxymonosulfate (PMS) for contaminants degradation. However, the mechanism of activation is not fully understood. This study aims to elucidate the mechanism of PMS activation by nano-CuFe2O4 and its implications for polychlorinated biphenyls (PCBs) degradation. PMS was found to be efficiently activated by nano-CuFe2O4 to produce free radicals for PCB28 degradation at a wide range of pH values. Electron paramagnetic resonance and free radical quenching studies were used to elucidate the mechanism of PMS activation by nano-CuFe2O4. It emerged that superoxide radical anions (O-2(center dot-)) generated by nano-CuFe2O4 could transfer electrons to Fe(III) and Cu(II), generating Fe(II) and Cu(I) on the nano-CuFe2O4 surface. The generated Fe(II) and Cu(I) further activated PMS to produce sulfate (SO4 center dot-) and hydroxyl ((OH)-O-center dot) radicals for PCB28 degradation. The addition of quencher of O-2(center dot-) significantly inhibited PCB28 degradation, while increasing dissolved oxygen concentration enhanced PCB28 degradation, which further confirmed the key role of O-2(center dot-) in SO4 center dot- and (OH)-O-center dot generation. Based on intermediate identification, a PCB28 degradation pathway was proposed. These findings provide new insight into the mechanism of heterogeneous activation of PMS by nano-CuFe2O4 and will promote its application in the degradation of refractory organic compounds.