Background and objectives: Currently, we have a shortage of comprehensive information about newer antiepileptic drugs (AEDs) in the pediatric population. This might explain the discrepancies among pediatricians’ preferences in this regard. Therefore, it is crucial to study the multifaceted impacts of these drugs on children. The endpoints of our study were non-AED predictors of the requirement of combination therapy for seizure management, seizure-free period >6 months and >12 months, change in Quality of Life in Childhood Epilepsy Questionnaire - 55 (QOLCE-55), and incidence of adverse events.Methods: This prospective, observational study was conducted in KIMS, Bhubaneswar, India, from January 2021 to November 2022. Children of 2-12 years of age were treated with monotherapy of either newer antiepileptics, e.g., levetiracetam, topiramate, and oxcarbazepine or older antiepileptics, e.g., valproic acid, phenytoin, phenobarbital, and carbamazepine. Univariate and multivariate analyses were performed for the assessment of predictors. We used R software (version 4.1.1) for data analysis.Results: One hundred and ninety-eight (91.7%) of 216 enrolled participants completed this study. The mean age of the study population was 5.2 years and 117 (59%) of them were males. The univariate analysis showed that male gender, low birth weight, preterm birth, assisted vaginal delivery and site-specific epilepsy, and maternal history of epilepsy were significant predictors of combination therapy and reduced seizure-free period. There was a non-significant difference regarding the improvement of QOLCE-55 scores. None of the adverse events were serious.Conclusions: Perinatal complications and maternal history of epilepsy contribute significantly toward the efficacy of antiepileptics. However, multivariate analysis did not yield statistically significant results.