Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1β (IL-1β) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of anti-inflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1β-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-α) in human chondrocytes. Trelagliptin ameliorates IL-1β-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1β-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1β-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9- reduction by IL-1β. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA. Copyright © 2021. Published by Elsevier Ltd.