Abstract Epilepsy comes after stroke as the most common chronic neurological disorder worldwide. Inflammation enhances neuronal hyperexcitability that could provide a background setting for the development of epilepsy. The aim of this study was to assess the effect of valproate (VAL), diclofenac (DIC), meloxicam (MEL), VAL + MEL and VAL + DIC in pentylenetetrazol (PTZ) kindled mice. Seventy mice were randomly allocated into 7 equal groups; Control, PTZ, VAL, DIC, MEL, VAL +MEL and VAL + DIC groups. Kindling was induced by PTZ (40 mg/kg, i.p.) injection every other day for 17 days. The drugs were administered, 30 min before each PTZ injection till the end of the schedule. Seizure score, latency, duration and mortality rate were recorded in all groups. Tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA) and prostaglandin E2 (PGE2) levels as well as reduced glutathione (GSH) content were assessed in brain homogenate at the end of the schedule. VAL, DIC, MEL, VAL + MEL and VAL + DIC decreased seizure score and duration. Meanwhile, they increased the latency period. PTZ increased TNF-α, IL-1β, MDA, and PGE2 levels meanwhile, it decreased GSH content. Administration of VAL, DIC, MEL, VAL + MEL and VAL + DIC decreased TNF-α, IL-1β, MDA, and PGE2 levels meanwhile, they increased GSH content in the brain homogenates. Effects of VAL + DIC combination on the studied parameters were significant in relation to VAL. VAL, DIC, MEL, VAL + MEL and VAL + DIC produced anticonvulsant effect and mitigated inflammation and oxidative stress in PTZ-kindled mice. Interestingly, DIC rather than MEL enhanced the anticonvulsant effect VAL.