Background: Children and adolescents are major computer and technology gadget users. While serious games hold important promises for promoting health-related behavioral change and mental health among children and adolescents, their efficacy is yet unclear. Objectives: We conducted a systematic review and meta-analysis aimed to offer a comprehensive picture on the evidence-based status of serious games for mental health promotion and health-related behavioral change in children and adolescents. Method: We included 34 clinical and experimental randomized studies investigating the efficacy of serious games on mental health promotion and health-related behavioral change in children and adolescents. Results: Results showed a small, but significant effect size with very high heterogeneity. Participants' age, number of sessions, the length of session, and study quality significantly moderated the effect size, with younger participants, fewer and shorter sessions, and lower quality of the study being associated with higher effect sizes. The effect size was not significant for follow-up measurements. Conclusions: The evidence supporting the use of serious games in children and adolescents for purposes of health promotion is limited. These conclusions must be considered with caution given the bias of publication. We need more adequately conducted studies testing well-specified serious games before we can draw clear conclusions.