BackgroundOsteoarthritis (OA) is a progressive joint condition marked by the slow degradation of articular cartilage. Vinpocetine (Vin), a synthetic derivative of vincamine derived from the vinca plant, exhibits anti-inflammatory and antioxidant properties. Nevertheless, the specific role and mechanism of Vin in the treatment of OA remain largely unexplored. ObjectivesThe study is designed to uncover the impacts of Vin on tert‑butyl hydroperoxide (TBHP)-induced ferroptosis and to explore its potential role and underlying mechanisms in the treatment of OA. Concurrently, we established an OA mouse model through medial meniscal instability surgery to assess the therapeutic effects of Vin in vivo. MethodsThrough network pharmacology analysis, we have identified the key targets and potential pathways of Vin. To simulate an oxidative stress-induced OA environment in vitro, we induced chondrocyte injury using TBHP. We tested how Vin affects chondrocytes under TBHP induction by DHE and DCFH-DA probes, BODIPY-C11 and FerroOrange staining, mitochondrial function assessment, Western blotting, co-immunoprecipitation, and immunofluorescence techniques. Simultaneously, we established an OA mouse model through medial meniscal instability surgery to assess the in vivo therapeutic effects of Vin. In this model, we used X-ray and micro-CT imaging, SO staining, TB staining, H&E staining, and immunohistochemistry to analyze the role of Vin in detail. ResultsThis study demonstrated that Vin effectively suppressed TBHP-induced ferroptosis and extracellular matrix (ECM) degradation and significantly lessened mitochondrial damage associated with ferroptosis. In the OA mouse model, Vin improved cartilage degeneration, subchondral remodeling, synovitis, and ECM degradation. Vin worked by activating the Nrf2/GPX4 pathway and inhibiting the Keap1-Nrf2 interaction. This study focused on the function of ferroptosis in OA and its influence on chondrocyte damage and disease progression, offering novel perspectives on potential treatments. ConclusionVin activated the Nrf2/GPX4 pathway, thereby slowing OA progression, inhibiting ferroptosis, and preventing ECM degradation.