Background <p>This study aimed to evaluate the persistence and treatment modification patterns of three commonly used selective serotonin reuptake inhibitors (SSRIs)—fluoxetine, escitalopram, and sertraline—in children and adolescents with depression.</p> Methods <p>We conducted a nationwide population-based retrospective cohort study using the Health Insurance Review and Assessment Service database of South Korea (2007–2019). Patients aged 5–19 years who were newly prescribed one of three SSRIs between 2009 and 2018 were included. During a one-year follow-up period, we assessed treatment persistence and categorized treatment changes as simple discontinuation, switching, combination with another antidepressant, and augmentation with antipsychotics. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated via Cox proportional hazards models.</p> Results <p>Only approximately 3% of patients remained on their initial SSRIs after one year, with most treatment changes occurring due to simple discontinuation, followed by switching, augmentation, and combination. Fluoxetine was associated with the lowest risk of treatment modification, particularly for combination and augmentation. The lowest switching rates were associated with escitalopram, whereas the lowest risk of simple discontinuation was associated with sertraline. Sociodemographic and clinical factors, including psychiatric comorbidities, significantly influence treatment patterns.</p> Conclusions <p>Each SSRI exhibited distinct patterns of treatment modifications, with no single agent consistently outperforming the other agents. These findings highlight the need for individualized SSRI selection that considers both pharmacological profiles and patient characteristics in the real-world management of pediatric depression.</p> Clinical trial number <p>Not applicable.</p>