Objective: The present study was undertaken to investigate the effect of long dose administration of methanol rhizome extract of Podophyllum hexandrum and hydrogen peroxide on lipid peroxidation of erythrocytes, antioxidant enzyme status of rat liver, kidney, lung and brain tissue and body weight and organ weight changes of albino rats. Methods: The body and organ weight was monitored with digital scale balance and lipid peroxidation of RBC ghost membrane was monitored by measuring malonaldehyde (MDA). Antioxidant enzymes were assayed by standard procedures. Results: Our study showed that administration of H2O2 (0.1%) in drinking water of the rats for 25 weeks increased the malondialdehyde levels in erythrocytes of all the rats. However, rats receiving Podophyllum hexandrum extract and α- tocopherol had lower MDA levels in a dose dependent manner, which indicates decreased lipid peroxidation in these rats. Our results also showed decrease in the activity of glutathione reductase, glutathione-S-transferase and reduced glutathione levels in different organs of H2O2 treated rats. Rats receiving methanolic extract of Podophyllum hexandrum at the concentration of 5, 10 and 15mg% for 25 weeks increased the activity of glutathione reductase, glutathione-S-transferase and glutathione levels in different organs of the rats indicates the protective effect of the plant in combating oxidative stress undergone by the rats. No significant variation (P< 0.05) in the organ weights between the control and the treated groups was observed after 25 weeks of treatment. Conclusions: In conclusion, this study presents strong evidence of the nontoxic effect of the methanol extract of Podophyllumhexandrum. The findings also demonstrate that Podophyllum hexandrum methanol extract increased the levels of antioxidant enzymes and decreased lipid peroxidation in albino rats and explained the extensive utilization of the plant in traditional medicine.