〔Abstract〕 Objective To investigate the role and possible mechanism of curcumin(Cur) regulating Peroxiredoxin-6(Prdx6) expression in inhibiting Erastin-induced ferroptosis in C28/I2 chondrocytes. Methods Safranin O/Fast Green and hematoxylin-eosin(HE) staining were performed to observe the pathological changes in the knee joint of rats with osteoarthritis(OA). The expression levels of Prdx6 and GPX4 proteins in cartilage tissues with OA were detected by immunohistochemistry and Western blot. C28/I2 chondrocytes were treated with different concentrations of Cur, cell viability was detected by thiazolyl blue tetrazolium bromide(MTT) assay and cytotoxicity was measured by lactic dehydrogenase(LDH) assay. The production of lipid reactive oxygen species(ROS) in chondrocytes was detected by flow cytometry, and the total glutathione(GSH) assay kit was used to detect the GSH level in chondrocytes. Western blot was performed to detect the expression level of Prdx6 and ferroptosis-related proteins in chondrocytes. The interaction between the Cur molecule and Prdx6 was analyzed through the molecular docking technique. Results During the OA progression, OA rats and OA patients showed pathological changes such as damage to the cartilage and a decrease in the number of chondrocytes. The expression levels of Prdx6 and GPX4 were reduced in the cartilage tissues of OA patients compared with healthy people. Further study revealed that the treatment of Erastin-induced ferroptosis in C28/I2 chondrocytes in a mouse model with 20 μmol/L of Cur could improve cell viability, decrease cytotoxicity, inhibit lipid ROS production, and increase the level of intracellular GSH. Western blot results showed decreased expression of Prdx6, SLC7A11, FTH, and GPX4 and increased expression of ACSL4. In addition, Cur molecules interacted with Prdx6 protein by van der Waals forces and π bond. Conclusion Cur may inhibit Erastin-induced ferroptosis in C28/I2 chondrocytes by upregulating the Prdx6 expression level.