Abstract: In the present study, we aimed to investigate the protective effect of puerarin (PR) on the substantia nigra (SN) of 6-hydroxydopamine (6-OHDA)-lesioned rats. Our results show that glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were increased, while the malonaldehyde (MDA) content was reduced in the SN following PR treatment. Furthermore, examination of specific immunostaining revealed that histopathological lesions in SN tissue were alleviated. Similarly, the mRNA level of heme oxygenase-1 (HO-1) was notably decreased, and the expression of NAD(P)H: quinone oxidoreductase-1 (NQO-1) mRNA was increased. As revealed by Western blot analysis, PR therapy contributed to a marked expression of DJ-1 and superoxide dismutase-2 (SOD2) at the protein levels in the SN of 6-OHDA-lesioned rats. Taken together, these findings suggest that puerarin effectively exerts its neuroprotective action against 6-OHDA-induced Parkinsonian rats through the enhancement of antioxidant capability and attenuation of oxidative stress injury, thereby inhibiting neurodegeneration in SN tissue. [Copyright &y& Elsevier]