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IntroductionWhile vaccines are crucial for disease prevention, disparities in vaccination coverage persist among youths aged 10 to 29 years, including within the United States. Serious games are emerging as a new strategy to address vaccine hesitancy. This systematic review aimed to aggregate and assess the current evidence on game-based interventions to improve youth vaccination rates, evaluating their impact and identifying factors influencing their effectiveness. MethodsThis systematic review was conducted through a meticulous search and evaluation of literature from databases including PubMed, Cumulative Index to Nursing and Allied Health Literature database, ProQuest platform, Cochrane Library, and Google Scholar. Studies were included if they (a) were designed with the purpose of improving youth vaccination rates; (b) were published in English; (c) were published between January 2011 and June 2023; and (d) evaluated the effect of game-based interventions. Search terms included Medical Subject Headings terms and keywords of the eligible articles. ResultsOut of 269 studies, 11 were included in the final analysis of this review. The earliest study dated back to 2013, with 5 being randomized controlled trial and 6 studies incorporating theoretical models in their design or outcome measures. The findings indicated a generally positive effect of game-based interventions on vaccine-related knowledge. However, the impact on actual vaccine uptake was limited. In-game avatar customization and collaboration games were found as effective tools for player engagement. ConclusionThe review findings indicated that serious games boost vaccine knowledge but lack strong evidence for influencing youth vaccine uptake. More rigorous research and tailored game designs are needed to determine the effectiveness of game-based interventions and effectively address the diverse needs of youth in vaccine decision-making.