Physical exercise and riluzole have been shown to affect epilepsy. A systemic kainic acid (KA) injection (20mg/kg) in mice evoked seizure activity within 10 min with wet dog shakes (WDS) and focal convulsion. Physical exercise proceeded by swimming for 6 weeks, and riluzole (5mg/kg) was injected 30 min before KA. Both the riluzole-treated group and the exercised group experienced decreased seizure activity 10 min after KA injection and maintained seizure activity rating scores of 2-3 for 2 h afterwards. To examine whether riluzole and exercise had synergistic effects, we exercised animals and then treated them with riluzole 30 min before KA administration. The riluzole and exercise group experienced decreases in seizure activity by two rating scores, and the regimen did not lead to death. Additionally, riluzole and physical exercise group experienced decreased rates of seizure induction, mortality, and motor impairment. Our results suggest that clonidine attenuates the protective effects of physical exercise, vis-a-vis KA-induced seizures.