Abstract: Objective To investigate the protective mechanism of resveratrol （Res） against the CoCl₂-induced hypoxia injury in the skeletal muscle cells. Methods According to different intervention methods, the murine skeletal muscle C2C12 cells were divided into the control, CoCl₂, Res and CoCl₂+Res groups, respectively. The cell morphology was observed after myosin heavy chain （MyHC） immunofluorescence staining. The fusion index of the myotubes was calculated. The expression level of MyHC mRNA was detected by quantitative fluorescence PCR. The expression levels of hypoxia-inducible factor-1α （HIF-1α）, Bcl2/ adenovirus E1B interacting protein 3 （BNIP3）, microtubule associated protein 1 light chain 3 （MAP1LC3, LC3）, p62 and Beclin1 proteins were measured by Western blot. Results After CoCl₂-induced hypoxia, the morphology of myotubes was abnormal and the quantity of differentiated myotubes was reduced. Compared with the control group, the fusion index of differentiated myotubes was significantly decreased （P < 0.001）, the expression levels of MyHC mRNA and protein were significantly down-regulated （both P < 0.05）, those of HIF-1α, BNIP3 and Beclin1 proteins and LC3 were significantly up-regulated （all P < 0.001）, and that of p62 protein was significantly down-regulated （P < 0.001） in the CoCl₂ group, respectively. Following the Res intervention, the cellular morphology was recovered and the quantity of differentiated myotubes was increased. Compared with the CoCl₂ group, the fusion index of differentiated myotubes was significantly elevated, the expression levels of mRNA of MyHC subtypes （Myh7, Myh2 and Myh4） and MyHC protein were significantly up-regulated, those of HIF-1α, BNIP3 and Beclin1 proteins were significantly down-regulated, and that of p62 protein was significantly up-regulated （all P < 0.05）. Conclusions CoCl₂-induced hypoxia can down-regulated the expression of MyHC, resulting in decreased muscle differentiation and fusion. Rescan enhance the differentiation and fusion of myoblasts under hypoxia condition, and extert protective effect upon the repair of muscle cell injury probably by suppressing the autophagy induced by the HIF-1α/BNIP3 signaling pathway, thereby accelerating the repair of muscle cell injury.