BACKGROUND: Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking. In this study, the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice, which is a cost-effective mechanism for screening of antiseizure drugs. METHODS: The impact of lacosamide (5 mg/kg) and perampanel (0.125 mg/kg) alone and their combination was tested in corneal kindling process (3-mA current for 3 s applied twice daily for consecutive 12 days) in male BALB/c mice. Post-kindling, mice were subjected to a battery of behavioral tests assessing anxiety, memory, and depression-like behaviors. Brain tissues were then harvested for analysis of oxidative stress biomarkers. RESULTS: Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs. Animals treated with combination therapy showed significant behavioral improvements, as reduced anxiety and depression were noticed, and their cognitive abilities were notably better compared to animals of all other groups. Moreover, biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress. In addition, outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress. CONCLUSIONS: This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.