Cigarette smoking is concerned as a major risk factor in the development of various neurological disorders. Oxidative stress is suggested as a possible contributing factor in the pathogenesis of cigarette smoking-induced toxicity. Therefore, the present study was intended to evaluate the neuroprotective role of Sesbania grandiflora (S. grandiflora) against chronic cigarette smoke induced oxidative damage in rat brain. Adult male Wistar-Kyoto rats were exposed to cigarette smoke for a period of 90 days and consecutively treated with S. grandiflora aqueous suspension (SGAS, 1,000 mg/kg body weight per day by oral gavage) for a period of 3 weeks. Lipid peroxidation and antioxidants status were analyzed in the brain. Rats exposed to cigarette smoke showed significant increase in conjugated diens (CD), hydroperoxides (HP) and malendialdehyde (MDA) levels with concomitant decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH) activities and the levels of reduced glutathione (GSH), vitamin C and vitamin E. Also cigarette smoke-exposure resulted in a marked increase in copper and decrease in zinc, manganese and selenium levels in brain. Administration of SGAS attenuates lipid peroxidation, enhanced the antioxidant status, restored the levels of micronutrients and retained the brain histology. The results of our study indicate that chronic cigarette smoke-exposure accelerates oxidative stress, thereby disquieting the brain defensive mechanism and S. grandiflora protects the brain from the oxidative damage through its biopotency.