Background: Epilepsy is a common neurological disorder in adolescents, often associated with anxiety and depression, significantly impacting their quality of life (QoL). This study aimed to compare the QoL of adolescents with epilepsy receiving monotherapy and polytherapy and identify factors affecting their health-related QoL. This study aimed to assess the QoL of adolescents with epilepsy receiving monotherapy or polytherapy and determine the influencing factors on their health-related QoL. Methods: This comparative cross-sectional study included adolescent patients with epilepsy, aged 10-18 and with an average IQ of 90-110, from Benha University Hospital and Benha Children Hospital (May to November 2022). Results: The monotherapy group exhibited significantly lower generalized seizures and fit frequency compared to the polytherapy group. However, QoL domains did not significantly differ between the two groups. In both groups, age, weight, and height showed negative correlations with QoL scores. Multivariate regression analysis revealed that none of the studied factors significantly predicted KIDSCREEN-27 scores. Conclusion: No significant differences in quality of life and social well-being between adolescents with epilepsy receiving mono antiepileptic therapy and those receiving poly antiepileptic therapy. Both treatment groups had comparable scores in the KIDSCREEN-27 domains.