Peripheral nerve injury is known to activate the hypoxia-inducible factor-1 alpha (HIF-1 alpha) pathway as one of pro-regenerative transcriptional programs, which could stimulate multiple injury-induced gene expression and contribute to axon regeneration and functional recovery. However, the role of HIF-1 alpha in peripheral nerve regeneration remains to be fully elucidated. In this study, rats were divided into three groups and treated with sham surgery, surgery with cobalt chloride (CoCl2) and surgery with saline, respectively. Sciatic functional index, morphologic evaluations of muscle fibers, and never conduction velocity were performed to measure the functional recovery at 12 weeks postoperatively. In addition, the effects of CoCl2 on the expression of HIF-1 alpha, glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were determined at mRNA levels; as well as HIF-1 alpha, the dual leucine zipper kinase (DLK), the c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), BDNF and NGF were measured at protein level at 4 weeks postoperatively. Systemic administration of CoCl2 (15 mg/kg/day intraperitoneally) significantly promoted functional recovery of rats with sciatic nerve transection injury. This study demonstrated in rats treated with CoCl2, the expression of HIF-1 alpha, GDNF, BDNF and NGF was significantly increased at mRNA level, while HIF-1 alpha, DLK, p-JNK, BDNF and NGF was significantly increased at protein level.