AbstractOsteoarthritis, a chronic degenerative cartilage disease, is the leading cause of movement disorders among humans. Although the specific pathogenesis and associated mechanisms remain unclear, oxidative stress‐induced metabolic imbalance in chondrocytes plays a crucial role in the occurrence and development of osteoarthritis. In this study, a trimanganese tetroxide (Mn3O4) nanozyme with superoxide dismutase (SOD)‐like and catalase (CAT)‐like activities is designed to reduce oxidative stress‐induced damage and its therapeutic effect is investigated. In vitro, Mn3O4nanozymes are confirmed to reprogram both the imbalance of metabolism in chondrocytes and the uncontrolled inflammatory response stimulated by hydrogen peroxide. In vivo, a cross‐linked chondroitin sulfate (CS) hydrogel is designed as a substrate for Mn3O4nanozymes to treat osteoarthritis in mouse models. As a result, even in the early stage of OA (4 weeks), the therapeutic effect of the Mn3O4@CS hydrogel is observed in both cartilage metabolism and inflammation. Moreover, the Mn3O4@CS hydrogel maintained its therapeutic effects for at least 7 days, thus revealing a broad scope for future clinical applications. In conclusion, these results suggest that the Mn3O4@CS hydrogel is a potentially effective therapeutic treatment for osteoarthritis, and a novel therapeutic strategy for osteoarthritis based on nanozymes is proposed.