BACKGROUND: Digital health interventions (DHIs) are defined as digital technologies such as digital health applications and information and communications technology systems (including SMS text messages) implemented to meet health objectives. DHIs implemented using various technologies, ranging from electronic medical records to videoconferencing systems and mobile apps, have experienced substantial growth and uptake in recent years. Although the clinical effectiveness of DHIs for children and adolescents has been relatively well studied, much less is known about the cost-effectiveness of these interventions. OBJECTIVE: This study aimed to systematically review economic evaluations of DHIs for pediatric and adolescent populations. This study also reviewed methodological issues specific to economic evaluations of DHIs to inform future research priorities. METHODS: We conducted a database search in PubMed from 2011 to 2021 using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. In total, 2 authors independently screened the titles and abstracts of the search results to identify studies eligible for full-text review. We generated a data abstraction procedure based on recommendations from the Panel on Cost-Effectiveness in Health and Medicine. The types of economic evaluations included in this review were cost-effectiveness analyses (costs per clinical effect), cost-benefit analyses (costs and effects expressed in monetary terms as net benefit), and cost-utility analyses (cost per quality-adjusted life year or disability-adjusted life year). Narrative analysis was used to synthesize the quantitative data because of heterogeneity across the studies. We extracted methodological issues related to study design, analysis framework, cost and outcome measurement, and methodological assumptions regarding the health economic evaluation. RESULTS: We included 22 articles assessing the cost-effectiveness of DHI interventions for children and adolescents. Most articles (14/22, 64%) evaluated interventions delivered through web-based portals or SMS text messaging, most frequently within the health care specialties of mental health and maternal, newborn, and child health. In 82% (18/22) of the studies, DHIs were found to be cost-effective or cost saving compared with the nondigital standard of care. The key drivers of cost-effectiveness included population coverage, cost components, intervention effect size and scale-up, and study perspective. The most frequently identified methodological challenges were related to study design (17/22, 77%), costing (11/22, 50%), and economic modeling (9/22, 41%). CONCLUSIONS: This is the first systematic review of economic evaluations of DHIs targeting pediatric and adolescent populations. We found that most DHIs (18/22, 82%) for children and adolescents were cost-effective or cost saving compared with the nondigital standard of care. In addition, this review identified key methodological challenges directly related to the conduct of economic evaluations of DHIs and highlighted areas where further methodological research is required to address these challenges. These included the need for measurement of user involvement and indirect effects of DHIs and the development of children-specific, generic quality-of-life outcomes.