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 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. Patients were divided into two groups: Group I (n = 50): Adolescents with epilepsy receiving mono antiepileptic therapy and Group II (n = 50): Adolescents with epilepsy receiving poly antiepileptic therapy.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. 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.