Developing nanozymes with effective reactive oxygen species (ROS) scavenging ability is a promising approach for osteoarthritis (OA) treatment. Nonetheless, numerous nanozymes lie in their relatively low antioxidant activity. In certain circumstances, some of these nanozymes may even instigate ROS production to cause side effects. To address these challenges, a copper‐based metal–organic framework (Cu MOF) nanozyme is designed and applied for OA treatment. Cu MOF exhibits comprehensive and powerful activities (i.e., SOD‐like, CAT‐like, and •OH scavenging activities) while negligible pro‐oxidant activities (POD‐ and OXD‐like activities). Collectively, Cu MOF nanozyme is more effective at scavenging various types of ROS than other Cu‐based antioxidants, such as commercial CuO and Cu single‐atom nanozyme. Density functional theory calculations also confirm the origin of its outstanding enzyme‐like activities. In vitro and in vivo results demonstrate that Cu MOF nanozyme exhibits an excellent ability to decrease intracellular ROS levels and relieve hypoxic microenvironment of synovial macrophages. As a result, Cu MOF nanozyme can modulate the polarization of macrophages from pro‐inflammatory M1 to anti‐inflammatory M2 subtype, and inhibit the degradation of cartilage matrix for efficient OA treatment. The excellent biocompatibility and protective properties of Cu MOF nanozyme make it a valuable asset in treating ROS‐related ailments beyond OA.