Purpose <p>This study aimed to evaluate the therapeutic effects of Omentin-1 on osteoarthritis and explore its protective mechanisms.</p> Methods <p>Two osteoarthritis mouse models were created: wild-type and SIRT6^−/−. After five weeks of Omentin-1 injection, we evaluated M1 and M2 macrophage distribution in the mouse synovium and measured inflammatory factor levels. Matrix proteins related to cartilage repair were detected, and safranin O-green and toluidine blue staining were used to evaluate the repair. Furthermore, we evaluated how Omentin-1 regulated macrophage polarization and explored potential mechanisms.</p> Result <p>Omentin-1 was low in osteoarthritis mice and linked to M1 macrophage polarization. It protected these mice by reducing synovial inflammation, decreasing M1 macrophages, increasing M2 macrophages, and lowering pro-inflammatory factors while raising anti-inflammatory factors and minimizing inflammatory cell infiltration in the synovium. Omentin-1 enhanced Collagen II and α-SMA expression in cartilage, aiding repair. Further mechanistic studies indicated that Omentin-1 can enhance the expression of SIRT6 in the joint tissues of mice with osteoarthritis. Omentin-1’s inhibition of inflammation in osteoarthritis mice was linked to SIRT6.</p> Conclusion <p>Elevated Omentin-1 levels can mitigate the inflammatory response in osteoarthritis by enhancing SIRT6 expression, inhibiting inflammatory factors, suppressing M1 macrophages, and increasing M2 macrophages.</p>