Abstract The increasing resistance risks of conventional antibiotic abuse and the formed biofilm on the surface of wounds have been demonstrated to be the main problems for bacteria‐caused infections and unsuccessful wound healing. Treatment by reactive oxygen species, such as the commercial H 2 O 2 , is a feasible way to solve those problems, but limits in its lower efficiency. Herein, an ionic covalent‐organic framework‐based nanozyme (GFeF) with self‐promoting antibacterial effect and good biocompatibility has been developed as glucose‐triggered cascade catalyst against bacterial wound infection. Besides the efficient conversion of glucose to hydrogen peroxide, the produced gluconic acid by loading glucose oxidase can supply a compatible catalytic environment to substantially improve the peroxidase activity for generating more toxic hydroxyl radicals. Meanwhile, the adhesion between the positively charged GFeF and the bacterial membrane can greatly enhance the healing effects. This glucose‐triggered cascade strategy can reduce the harmful side effects by indirectly producing H 2 O 2 , potentially used in the wound healing of diabetic patients.