Osteochondral defects (OCD) cannot be efficiently repaired due to the unique physical architecture and the pathological microenvironment including enhanced oxidative stress and inflammation. Conventional strategies, such as the control of implant microstructure or the introduction of growth factors, have limited functions failing to manage these complex environments. Here we developed a multifunctional silk-based hydrogel incorporated with metal-organic framework nanozymes ([email protected]) to provide a suitable microenvironment for enhanced OCD regeneration. The incorporation of CuTA nanozymes endowed the SF hydrogel with a uniform microstructure and elevated hydrophilicity. In vitro cultivation of mesenchymal stem cells (MSCs) and chondrocytes showed that [email protected] hydrogel accelerated cell proliferation and enhanced cell viability, as well as had antioxidant and antibacterial properties. Under the inflammatory environment with the stimulation of IL-1β, [email protected] hydrogel still possessed the potential to promote MSC osteogenesis and deposition of cartilage-specific extracellular matrix (ECM). The proteomics analysis further confirmed that [email protected] hydrogel promoted cell proliferation and ECM synthesis. In the full-thickness OCD model of rabbit, [email protected] hydrogel displayed successfully in situ OCD regeneration, as evidenced by micro-CT, histology (HE, S/O, and toluidine blue staining) and immunohistochemistry (Col I and aggrecan immunostaining). Therefore, [email protected] hydrogel is a promising biomaterial targeted at the regeneration of OCD. © 2022 The Authors.