The present study was designed to investigate the possible protective effects of catechin and rutin and their possible mechanisms of action in guarding against the oxidative stress and inflammation induced by ionizing radiation and/or cigarette smoke extract in rats. Exposure of rats to acute doses of γ-radiation or administration of cigarette smoke extract (CSE) in this study were found to exert an oxidative stress due to generation of ROS, which are characterized by elevation in MDA and nitric oxide levels and depletion in reduced glutathione, as well as elevation in MPO activity and level of TNF-α. The results also showed that activities of ALT, AST, ALP, and LDH were increased. Damaging effects were significantly increased in animals exposed to gamma radiation combined with administration of cigarette smoke extract in comparison to either irradiation or administration of cigarette smoke extract. Pretreatment with catechin or rutin largely protected against the change in all the measured parameters. Conclusion: Catechin and rutin might have the potential to modulate the damage induced by radiation exposure in cigarette smoke-treated animals.