Background: Montelukast, a selective reversible cysteinyl leukotriene1 (CysLT1) receptor antagonist, is used in treatment of asthma, exercise induced-bronchospasm, allergic rhinitis and urticaria. It was shown to protect against cerebral ischemia/reperfusion injury. Objectives: To examine the possible anticonvulsant effect of montelukast, either alone or in combination with a known antiepileptic drug "valproate" against pentylenetetrazole (PTZ)-induced seizures. Methods: 112 adult male Swiss albino mice were used in the study and divided into two main groups, each containing 5 subgroups (Gp). The first main group "acute PTZ model (PTZ-a)" contains: Gp1 "vehicle-treated group" was injected with saline (10 ml/kg, intraperitoneally "i.p." in a single dose ), Gp2 "acute PTZ-control" injected with a single dose of PTZ (60 mg/kg, i.p.), Gp3 injected with valproate (50 mg/kg, i.p.) 30 minutes before PTZ, Gp4 injected with a single dose of montelukast (10 mg/kg, i.p.) 30 minutes before PTZ and Gp5 injected with both montelukast and valproate 30 minutes before PTZ administration. The second main group "kindling model (PTZ-k)" contains: Gp1 was injected with saline (i.p.) every other day for 17 days, Gp2 "PTZ-kindled control" received 9 PTZ injections in a dose of (40 mg/kg, i.p.) on alternate days for 17 days, Gp3 injected with valproate (50 mg/kg, i.p.) for 17 days, 30 minutes before PTZ, Gp4 daily injected with montelukast (10 mg/kg, i.p.) for 17 days 30 minutes before PTZ and Gp5 received both montelukast (10 mg/kg, i.p.) and valproate (50 mg/kg, i.p.) daily for 17 days, 30 minutes before administration of PTZ. Results: Single and repeated PTZ administration produced stage 4 seizures associated with a significant reduction in the brain level of reduced glutathione (GSH), concomittent with significant elevation in the brain levels of malondialdehyde (MDA), inteleukin1β (IL1β), tumor necrosis factor α (TNFα) and leukotriene D4 (LtD4). The use of valproate alone and its combination with montelukast suppressed the incidence of stage 4 seizures in acute PTZ induced convulsion while montelukast, valproate and their combination decreased the percentage of animals reaching stage 4 seizures in kindled mice. In both PTZ acute and kindled models, montelukast, valproate and their combined administration significantly elevated brain level of GSH and significantly decreased brain levels of MDA, IL1β, TNFα and LtD4 as compared to PTZ control groups. Interestingly, co-administration of valproate and montelukast resulted in a significant elevation in the brain level of GSH concomitant with a significant reduction in the brain levels of MDA, IL1β, TNFα and LtD4 as compared to each of the valproate and the montelukast groups in both models. Conclusion: Montelukast, either alone or in combination with valproate protects against PTZ induced seizures via blockade of leukotreine receptors & amelioration of oxidative stress and inflammatory cascades