Objective To explore the efficacy and safety of Perampanel (PER) monotherapy in children with focal epilepsy. Methods Forty-six children with focal epilepsy who were newly diagnosed in the Department of Neurology of Wuxi Children's Hospital and had not used anti-seizure medications during January 2021 to June 2022 were selected, including 24 males and 22 females, with an average age of (7.2 ± 2.4) years old. Mono-therapy of PER as the PER group (23 cases), mono-therapy of Levetiracetam (LEV) as the LEV group (23 cases). Compare the clinical efficacy and adverse reactions between the two groups. Result The total effective rate was 87.0% (20/23) in PER group and 73.9% (17/23) in LEV group after 3 months of treatment (P<0.05); the total effective rate in the PER group was 78.3% (18/23), and 60.9% (14/23) in the LEV group after 6 months of treatment (P<0.05). The differences were statistically significant. In the PER group, 2 children had adverse reactions, 1 case was lethargic, and 1 case was dizziness. By temporarily reducing the drug dose and slowing the rate of dosing, the adverse reactions disappeared. In LEV group, 3 children had adverse reactions, all of who were irritable in varying degrees. By slowing down the rate of drug addition, 2 children’s symptoms disappeared and 1 child's symptoms relieved during 3 ~ 6 months. Conclusion The new anti-seizure medication — PER has a better anti-epileptic effect on focal epilepsy, which is better than LEV. The adverse reactions of both drugs are less and mild, and can be selected according to clinical conditions.