Objective To investigate the effect of Huangqi Guizhi Wuwu Decoction on the serum levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nerve growth factor (NGF) and the mRNA expression of NGF in sciatic nerve tissue by establishing a rat model of diabetic peripheral neuropathy (DPN), as well as the possible mechanism of Huangqi Guizhi Wuwu Decoction in the treatment of DPN. Methods A rat model of DPN was established by 4-week high-fat diet and intraperitoneal injection of streptozotocin. Since week 5, the high-, middle-, and low-dose Huangqi Guizhi Wuwu Decoction groups were given Huangqi Guizhi Wuwu Decoction at a dose of 19.40,4.85, and 2.43 g/kg, respectively, by gavage, every day for 12 consecutive weeks; the mecobalamin group was given mecobalamin 0.25 mg/kg by gavage every day.RT-PCR was used to measure the mRNA expression of NGF in the sciatic nerve, and ELISA was used to measure the serum levels of IL-1β,TNF-α, and NFG. Results Compared with the normal group, the model group had significant increases in the serum levels of IL-1β and TNF-α (P<0.05) and significant reductions in the serum level of NGF and the mRNA expression of NGF in the sciatic nerve (P<0.05). Huangqi Guizhi Wuwu Decoction reduced the serum levels of IL-1β and TNF-α and increased in the serum level of NGF and the mRNA expression of NGF in the sciatic nerve in a dose-dependent manner. Conclusion Huangqi Guizhi Wuwu Decoction can alleviate inflammatory injury in peripheral nerves and promote the repair and regeneration of injured nerves, possibly by reducing the serum levels of IL-1β and TNF-α and upregulating the mRNA expression of NGF in the sciatic nerve in diabetic rats.