Bacterial pathogens pose a serious threat to human health, and there is an urgent need to develop highly effective antibacterial materials to eliminate the increasingly serious contamination of drug-resistant bacteria. Here, a Cu-doped ZIF-8 particle with unsaturated copper exhibits high peroxidase-like activity. 99.998% antibacterial efficiency against S. aureus can be achieved for 30 min at a low concentration of 50 μg·mL⁻¹, as well as complete sterilization against E. coli (up to 8 log). 99.999% antibacterial efficiency against Methicillin-resistant Staphylococcus aureus can be achieved, performing orders of magnitude higher than Vancomycin. The mechanism shows that the unsaturated Cu-N_x sites are enzyme-like active centers, which could promote the consumption of bacteria reducing substances by H₂O₂, and the generated *OH further aggravates bacterial oxidative stress and membrane damage. More importantly, the oxidation activity of adsorbed oxygen species on Cu-ZIF-8 is enhanced by charge transfer and structural changes between the ligand and copper center like natural enzymes. Cu-doped ZIF-8 with peroxidase-like activity shows great potential in antibacterial application and the revealed catalytic mechanism is helpful for understanding the high antibacterial activity of nanoparticles with Cu-N_x sites.