Low-grade and chronic inflammation is recognized as an important mediator of the pathogenesis of osteoarthritis (OA). The aim of current work was to test the therapeutic effects of gelsevirine on age-related and surgically induced OA in mice and elucidate the underlying mechanism. The in vitro studies revealed that gelsevirine treatment mitigated IL-1β-induced inflammatory response and degeneration in cultured chondrocytes, evidenced by reduced apoptosis and expression of MMP3, MMP9, MMP13, IFNβ, TNFɑ, and Il6, and increased expression of Col2A and Il10. Furthermore, gelsevirine treatment in IL-1β-stimulated chondrocytes reduced the protein expression of stimulator of IFN genes (STING, also referred to Tmem173) and p-TBK1. Importantly, gelsevirine treatment did not provide further protection in STING-deficient chondrocytes against IL-1β stimulation. The in vivo studies revealed that gelsevirine treatment mitigated articular cartilage destruction in age-related and destabilization of the medial meniscus (DMM)-induced OA. Similarly, gelsevirine treatment did not provide further beneficial effects against OA in STING deficient mice. Mechanistically, gelsevirine promoted STING K48-linked poly-ubiquitination and MG-132 (a proteasome inhibitor) reversed the inhibitive effects of gelsevirine on IL-1β-induced activation of STING/TBK1 pathway in chondrocytes. Collectively, we identify that gelsevirine targets STING for K48 ubiquitination and degradation and improves age-related and surgically induced OA in mice.