Nigella sativa (NS), an endogenous plant of family Ranunculaceae, exhibits a wide range of biological activity. This report explores the effect of aqueous extract of NS seeds on penicillin-(PCN-100 IU in 100 μl) induced epileptic rat model. Oral pretreatment of NS (250 mg/kg) suppressed PCN-induced seizure considerably, reduced spike-wave discharges and occurrence of generalized tonic-clonic seizures. Electroencephalographic data showed NS pretreatment to experimental animals elicited 85% abolition of high voltage spike discharges. NS pretreatment resulted in elevation of serotonin (5-HT) level and decreased dopamine (DA) level in cerebral cortex (CC), cerebellum (CB), caudate nucleus (CN) and midbrain (MB). A significant decrease in norepinephrine (NE) level was observed only in the CC. The present study suggests that chronic administration of NS protects PCN-induced generalized epilepsy by selectively altering the monoamine level in different brain regions. The seizure abolition observed in the NS pretreated rats was comparable to the anticonvulsive pattern exhibited by diazepam. The results suggest that NS has promising anticonvulsant action. © VSP 2005.