Objective: The purpose of this study was to systematically review the literature to assess if serious games impact health outcomes for children less than 18 years of age with chronic diseases. Additionally, the impact of self-efficacy, adherence, knowledge, use of theory, parent involvement, and study quality was also examined. Materials and Methods: Searches were conducted in databases EBSCO, PubMed, and Web of Science between June and August 2016. Randomized controlled trials using a serious game as an intervention, for participants under 18 years of age, to improve their chronic disease were included. Results: Data were extracted by two independent researchers, including: Title, author, and publication year; chronic disease; game description; number and age of participants; intervention duration; significant findings; parent involvement; theory; and study quality. Any disagreements were tackled and consensus was achieved. Eighteen studies were included in the review. The areas of health addressed included cerebral palsy, asthma, diabetes, developmental coordination disorders, and vision disorders. In these articles, eight health outcome variables were measured, including: lung function, glycemic control, hospital visits, motor proficiency, and visual acuity. Psychosocial variables that were assessed included self-efficacy and knowledge. Two articles included parents in the intervention, and three articles used theory. Six studies had significant health outcome finding, and four studies found a significant change in one psychosocial variable. Conclusion: This review demonstrates the potential for games to improve health outcomes of young individuals. However, the mixed results suggest that more serious game interventions need to be better designed and rigorously tested to support their impact on improving health outcomes.