Objective To identify two-year trajectories of health-related quality of life (HRQOL) among children with newly diagnosed epilepsy, and evaluate key predictors of HRQOL trajectories. Methods This study is part of a prospective study of adherence and HRQOL outcomes in children with epilepsy. Caregivers completed an HRQOL questionnaire at one month post diagnosis and every three months thereafter for two years. Chart review and additional questionnaires were used to collect medical variables and seizure outcomes. Results Participants included 120 children with epilepsy and their caregiver. Unique trajectories for overall HRQOL and PedsQL™ subscales were identified and were predominantly stable. A total side effects score emerged as a consistent predictor of all HRQOL domains. Other variables (i.e., socioeconomic status, seizures, internalizing and externalizing problems) uniquely predicted HRQOL domains. Conclusions Medical and psychosocial interventions should be implemented soon after treatment initiation to target modifiable factors (e.g., side effects, anxiety symptoms), which could improve HRQOL.