Background: Epilepsy is a chronic neurological disorder occurred due to periodic neuronal discharge and imbalance in brain electrical activity. 4-Hydroxy-TEMPO (Tempol) is a membrane-permeable radical scavenger moiety. Aim: The aim of this study is to evaluate the anticonvulsant potential of tempol against pentylenetetrazol (PTZ)-induced seizures in mice. Materials and Methods: Convulsion was produced in the male Swiss albino mice by administration of PTZ (90 mg/kg, i.p.). Mice were pretreated with either vehicle, tempol (50, 100 and 200 mg/kg, i.p.) or diazepam (5 mg/kg). Various behavioral, biochemical, molecular, and histological parameters were evaluated. Results: Mice pretreated with tempol (100 and 200 mg/kg) showed significantly (P < 0.01 and P < 0.001) delayed-onset on tonic-clonic convulsion, decrease the duration of convulsions and mortality in mice. Intraperitoneal administration of PTZ resulted in significant increase in oxido-nitrosative stress, whereas it significantly (P < 0.01 and P < 0.001) inhibited by the tempol administration. There was significant increased (P < 0.01 and P < 0.001) in the levels of brain monoamines (gamma-aminobutyric acid [GABA] and dopamine) and Na+ K+ ATPase activity, whereas significant decreased (P < 0.01 and P < 0.001) in xanthine oxidase activity in tempol pretreated mice. PTZ-induced up-regulated mRNA expressions of tumor necrosis factor-alpha, interleukin-1 beta , and c-Fos were significantly inhibited (P < 0.01 and P < 0.001) by tempol. It is also significantly down-regulated (P < 0.05 and P < 0.001) immunohistochemical c-Fos expressions. Conclusion: Pretreatment with tempol attenuates PTZ-induced tonic-clonic seizures via its anti-inflammatory, anti-oxidant and GABAergic potential.