AbstractThe development of non‐antibiotic pharmaceuticals with biocompatible and efficient antibacterial properties is of great significance for the treatment of bacterial keratitis. In this study, we have developed antibacterial iron‐doped nanozymes (Fe³⁺‐doped nanozymes, FNEs) with distinguished capacity to fight against bacterial infections. The iron‐doped nanozymes are composed of Fe³⁺ doped zeolitic imidazolate framework‐8 (Fe/ZIF‐8) and polyethylene imide (PEI), which were functionally coated on the surface of Fe/ZIF‐8 and imparted the FNEs with improved water dispersibility and biocompatibility. FNEs possess a significant spontaneous peroxidase‐mimic activity without the need for external stimulation, thus elevating cellular reactive oxygen species level by catalyzing local H₂O₂ at the infection site and resulting in bacteria damaged to death. FNEs eliminated 100% of Staphylococcus aureus within 6 h, and significantly relieved inflammation and bacterial infection levels in mice bacterial keratitis, exhibiting higher bioavailability and a superior therapeutic effect compared to conventional antibiotic eye drops. In addition, the FNEs would not generate drug resistance, suggesting that FNEs have great potential in overcoming infectious diseases caused by antimicrobial resistant bacteria.