Chondrocytes are well adapted to hypoxia and produce more functional extracellular matrix in low oxygen environments . In our previous study, methyltransferase SET domain containing (SETD)7 regulated chondrocyte activity in hypoxic conditions. However, the precise association between SETD7 and chondrocyte differentiation under low oxygen partial pressure remains unclear. The association between SETD7 and chondrocyte differentiation was studied by silencing SETD7 in chondrocytes . The results showed that the silencing of SETD7 in ATDC5 cells inhibited the Hippo signaling pathway, decreased Yes?associated protein (YAP) phosphorylation and increased the levels of YAP and hypoxia inducible factor?1α (HIF?1α) in the nucleus. YAP combined with HIF?1α to form a complex that promoted the expression of genes involved in chondrogenic differentiation and the glycolytic pathway. Thus, SETD7 inhibited chondrocyte differentiation and glycolysis via the Hippo signaling pathway. The present study demonstrated that SETD7 was a potential molecular target that maintained the chondrocyte phenotype during cartilage tissue engineering and cartilage?associated disease.