PURPOSE: To investigate the placebo effect in the treatment of children and adolescents with epilepsy. METHODS: We conducted a systematic review of studies comparing anti-seizure medication (ASM) to placebo in children and adolescents with epilepsy. Eligible studies were identified through the database PubMed following PRISMA guidelines resulting in the identification of 1173 articles. Screening and inclusion were assessed by two independent reviewers and 17 studies met inclusion criteria. RESULTS: Seventeen studies involving children and adolescents with epilepsy were included in this review. Compared to levetiracetam (LEV) and perampanel (PER), the placebo did not show a significant reduction in seizures. However, compared to pregabalin (PGB) the placebo was significant in reducing seizures at lower doses. Results for eslicarbazepine (ESL) were contradictory. Placebo-treated patients generally had lower Child Behavior checklist (CBCL) problem scores than those on LEV, which was associated with higher Total Problem Scores and worse Aggressive Behavior scores. Adverse event (AE) rates in the placebo groups varied widely, from 14 % to 91.8 %. CONCLUSION: This systematic review examined the effect of placebo treatment compared to ASMs in childhood epilepsy across 17 studies. The effectiveness of placebos was not significant compared to LEV and PER. However, there was a significant placebo effect compared to PGB, which was higher compared to low PGB doses than compared to high PGB doses. AE rates varied widely. Assessing long-term cognitive and behavioral outcomes was challenging due to short study durations and potential biases. Future research could play a critical role in preventing AEs in children undergoing ASM treatment by providing a deeper understanding of the placebo effect associated with these medications.