Osteoarthritis (OA) is the most prevalent form of human arthritis which is characterized by the degradation of cartilage and inflammation. As a rare Sirt6 activator, cyanidin is the major component of anthocyanins commonly found in the Mediterranean diet, and increasing evidence has shown that cyanidin exhibits anti-inflammatory effects in a variety of diseases. However, the anti-inflammatory effects of cyanidin on OA have not been reported. In the present study, we identified that cyanidin treatment could strongly suppress the expression of NO, PGE2, TNF-α, IL-6, iNOs, COX-2, ADAMTS5 and MMP13, and reduce the degradation of aggrecan and collagen II in IL-1β-induced human OA chondrocytes, indicating the anti-inflammatory effect of cyanidin. Further investigation of the mechanism involved revealed that cyanidin could upregulate the Sirt6 level in a dose-dependent manner and Sirt6 silencing abolished the effect of cyanidin in IL-1β-stimulated human OA chondrocytes, indicating a stimulatory effect of cyanidin on Sirt6 activation. Meanwhile, we found that cyanidin could inhibit the NF-κB pathway in IL-1β-stimulated human OA chondrocytes and its effect may to some extent depend on Sirt6 activation, suggesting that cyanidin may exert a protective effect through regulating the Sirt6/NF-κB signaling axis. Moreover, the in vivo study also proved that cyanidin ameliorated the development of OA in surgical destabilization of the medial meniscus (DMM) mouse OA models. In conclusion, these results demonstrate that cyanidin may have therapeutic potential for the treatment of OA.