Objectives This study was conducted to explore whether Hypericum perforatum L. (HPL) as a potent antioxidant protects against oxidative stress, cytokine production and caspase expression in muscle (soleus), brain and blood of sciatic nerve injury (SNI)-induced rats. Methods Thirty-five rats were equally divided into five groups. The first and second were used as untreated control and sham control groups, respectively. The third, fourth and fifth were sham + HPL, SNI and SNI + HPL groups, respectively. The third and fifth groups received 30 mg/kg HPL via gastric gavage for 28 days. Key findings High levels of muscle, brain and red blood cell (RBC) lipid peroxidation, plasma cytokine (TNF-alpha, IL-1 beta and IL-2), muscle PARP, caspase 3 and 9 expression levels were decreased by HPL treatments. Plasma glutathione peroxidase (GPx) activity, alpha-tocopherol and melatonin, muscle, brain and RBC reduced glutathione (GSH) concentrations were decreased by SNI induction, whereas their values were increased by HPL treatments. beta-carotene and retinol concentrations did not change in the five groups. Conclusion HPL may play a role in preventing SNI-induced inflammatory, oxidative and apoptotic blood, muscle and brain damages through upregulation of the GSH and GPx values but downregulation of PARP, caspase level and cytokine production in SNI-induced rats.