Background and Objective: The morbidity of pediatric epilepsy remains persistently high, with pharmacotherapy as a prevalent intervention. Perampanel aids in regulating neuronal overexcitation, yet there is scant research on its conjunction with conventional medications. To assess the clinical value of perampanel in the treatment of pediatric epilepsy and analyze the impact of interventions on the immune function and seizure frequency in affected children. Materials and Methods: Upon retrospectively selecting the clinical data from January, 2021 to June, 2023, pediatric epilepsy patients who received treatment in Ganzhou People's Hospital were collected as the research subjects. Forty cases undergoing treatment with levetiracetam were set as the control group and 40 cases receiving adjunctive perampanel were set as the research group. The clinical efficacy, epileptic seizure, discharge rate and serum levels of inflammatory factors before and after treatment were compared between the two groups. The incidence of adverse reactions was recorded and compared between the two groups. Results: The total effective rate of treatment in the research group was 97.50% (39/40), which was higher than 80.00% (32/40) in the control group (p<0.05). Before treatment, the differences in seizure frequency, seizure duration, NHS3 scores, P300 latency, wave amplitude, HMGB1 and TNF-alpha levels were not statistically significant between the two groups (p>0.05), while after treatment, children in the research group showed lower seizure frequency, shorter seizure duration, lower NHS3 score, shorter P300 latency, lower HMGB1 and TNF-alpha levels and higher wave amplitude compared with those in the control group (p<0.05). The total incidence of adverse reactions of children in the research group was 17.50% (7/40), which was not statistically significant compared with 15.00% (6/40) of children in the control group (p>0.05). Conclusion: The application of perampanel in the treatment of pediatric epilepsy is conducive to enhancing therapeutic outcomes, controlling the frequency and duration of seizures, reducing epileptic discharges, improving cognitive functions and lowering the serum levels of HMGB1 and TNF-alpha of pediatric patients. This approach exhibits a comparable safety profile to monotherapy, demonstrating a certain degree of clinical applicability for wider use.