Osteoarthritis (OA) is a common age‐related disorder. Chondrocytes in joint tissue play a critical role in normal articular cartilage function and tissue homeostasis. Local inflammatory cytokine‐induced chondrocyte senescence contributes to the development and progression of OA. Various dipeptidyl peptidase‐4 (DPP‐4) inhibitors have been widely used to treat type 2 diabetes. Here, we report a novel pharmacological role of the DPP‐4 inhibitor vildagliptin in chondrocyte senescence. Our data indicate that DPP‐4 is an inducible factor responsive to tumor necrosis factor‐α (TNF‐α) treatment in chondrocytes. The inhibition of DPP‐4 by vildagliptin ameliorates TNF‐α‐induced chondrocyte senescence as determined by cellular senescence‐associated β‐galactosidase (SA‐β‐Gal) activity. Vildagliptin displayed protective capabilities against TNF‐α‐induced chondrocyte cell cycle arrest in the G1 phase. Moreover, vildagliptin suppresses the three major TNF‐α‐induced chondrocyte senescence proteins including p53, p21, and plasminogen activator inhibitor‐1 (PAI‐1). Vildagliptin also suppresses TNF‐α‐induced p53 acetylation at K382. Consistently, our findings demonstrate the inhibitory effect of vildagliptin on p53 acetylation, which is mediated by sirtuin 1 (SIRT1) as the inhibition of SIRT1 negated the inhibitory action of vildagliptin on p53 acetylation. Furthermore, we found that the effect of vildagliptin on SIRT1 protection is adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) dependent, and the inhibition of AMPK activity negated the protection of vildagliptin against SIRT1 and chondrocytes senescence. In conclusion, our study explored the molecular mechanism and protective effect of the antidiabetic drug vildagliptin against chondrocyte senescence, and our findings imply that vildagliptin has a therapeutic potential in OA. © 2019 IUBMB Life, 1–2, 2019