The primary pathological changes observed in osteoarthritis (OA) involve inflammation and degeneration of chondrocytes. 3-phosphoglycerate dehydrogenase (Phgdh), a rate-limiting enzyme involved in the conversion of 3-phosphoglycerate to serine, serves as a crucial molecular component of cell growth and metabolism. However, its effects on chondrocytes in OA have not been determined. In the present study, a rat model of OA was used to investigate the expression levels of Phgdh in vivo and in vitro. Additionally, the role of Phgdh in extracellular matrix (ECM) synthesis, inflammation, apoptosis and oxidative stress levels of chondrocytes was detected in vitro. Phgdh expression was decreased in OA, and Phgdh overexpression promoted ECM synthesis, decreased levels inflammatory cytokines, such as Il-6, TNF-alpha, a disintegrin and metalloproteinase with thrombospondin motifs 5 and MMP13, and decreased apoptosis. Furthermore, expression of Phgdh effectively increased expression levels of the cellular antioxidant enzymes catalase and superoxide dismutase 1, and decreased the levels of reactive oxygen species in chondrocytes; and this may have been regulated by a Kelch like ECH associated protein 1/nuclear factor erythroid 2-related factor 2 axis. Taken together, these results suggest that Phgdh may be used to manage the progression of OA.