Osteoarthritis (OA) is a multifactorial and chronic disease describing the destruction of cartilage that can lead to defects in the elderly. There is currently no practical strategy that can reverse the OA process. Here, we describe nepetin, a small natural compound with extracellular matrix (ECM) and inflammation regulating functions. In this study, we investigated the therapeutic effects of nepetin on interleukin‐1β (IL‐1β)‐induced inflammation in mice chondrocyte and OA model. In chondrocytes, treatment with nepetin inhibited the overexpression of pro‐inflammatory cytokines and mediators induced by IL‐1β. Moreover, pretreatment or posttreatment with nepetin also reduced the ECM catabolism and enhanced the ECM anabolism. Mechanistically, nepetin suppressed NF‐κB signaling pathway in IL‐1β stimulated chondrocyte. Meanwhile, our molecular docking studies indicated nepetin had a powerful binding capacity to p65. Furthermore, nepetin showed a protective and therapeutic effect on the mouse OA model. To sum up, this study indicated nepetin had a new potential therapeutic option in OA. [ABSTRACT FROM AUTHOR]