In recent years, considerable emphasis has been focused on identifying new chemopreventive agents which could be useful for the human population. In the present study, we examined the protective role of mangiferin during experimental lung carcinogenesis with reference to its effect on DNA-damage and the detoxification enzyme system. The activities of detoxifying enzymes such as glutathione transferase (GST), quinone reductase (QR) and uridin 5′-diphosphate-glucuronosyl transferase (UDP-GT) were found to be decreased while the lipid peroxidation level was increased in the lung cancer bearing animals. Supplementation of mangiferin (100 mg/kg b.wt) enhanced the detoxification enzymes and reduced DNA damage as determined by single cell electrophoresis. Furthermore, the DNA–protein cross links which was found to be high in lung cancer bearing animals was also modulated upon supplementation with mangiferin. Our present results explain the unique association between the anti-oxidant effect of mangiferin and ultimately the capability of mangiferin to prevent cancer.