ObjectiveTo observe and compare the epileptic seizures, EEG changes and adverse reactions of perampanel and levetiracetam monotherapy in children with focal epilepsy. To explore the efficacy and safety of Perampanel monotherapy in the treatment of focal epilepsy and its relationship with miR-106b and autophagy related protein pathwaynide monotherapy in the treatment of focal epilepsy. Methods A total of 74 children with focal epilepsy in Xuzhou Children’s Hospital from March 2021 to December 2023 were selected as the research objects, all of whom were randomly divided into perampanel group and levetiracetam group. They were treated with perampanel and levetiracetam respectively. The clinical seizures, epileptiform discharges of EEG and adverse reactions were recorded and compared between the two groups. 2 mL of fasting peripheral blood were collected from the two groups of children in the morning, and the RNA of lymphocytes in the blood sample was extracted, the expression of miR-106b in peripheral blood lymphocytes of children was detected by qRT-PCR amplification, the levels of autophagy related protein Beclin-1, LC3-Ⅱ and p62 in the peripheral blood of children were detected by enzyme-linked immunosorbent assay. Results There was no significant difference in age, gender, BMI, course of disease, seizure frequency, epileptiform discharge index of EEG between the two groups (P>0.05). Seizure control: After treatment, the total effective rate and retention rate were 81.1% (30/37) and 78.4% (29/37) in the perampanel group and 59.5% (22/37) and 56.8% (21/37) in the levetiracetam group, respectively. The total effective rate in the perampanel group was higher than that in the levetiracetam group, with statistical difference (P<0.05). The retention rate in the perampanel group at 12 months was higher than that in the levetiracetam group, with statistical difference (P<0.05). EEG improvement: after treatment, the control improvement rate and total improvement rate of EEG in perampanel group were 32.4% (12/37) and 78.4% (29/37), and the control improvement rate and total improvement rate of EEG in levetiracetam group were 16.2% (6/37) and 56.8% (21/37), respectively, with statistical difference between the two groups (P<0.05). EEG in perampanel group was significantly improved. Adverse reactions: the incidence of adverse reactions in the perampanel group and Levetiracetam group was 10.8% (4/37) vs 24.3% (9/37). There was no statistical difference between the two groups (P>0.05). MiR-106b and autophagy related proteins: the expression of miR-106b, Beclin-1, LC3-Ⅱ in perampanel group was significantly decreased compared with that before treatment, with statistical differences (P<0.05). The expression of p62 was also increased compared with that before treatment, with obvious differences (P<0.05). There was no significant difference in the expression of miR-106b, Beclin-1, LC3-Ⅱ, p62 between levetiracetam group and perampanel group (P>0.05). Conclusion The clinical efficacy of perampanel as the first choice for the treatment of children with focal epilepsy is better than levetiracetam, which can effectively control seizures, improve the EEG of children, and has a low incidence of drug-related adverse events. Perampanel may exert antiepileptic effect by affecting miR-106b and autophagy related proteins.