2019 coronavirus disease (COVID-19) remains a pressing health concern, especially with lagging youth vaccination rates despite its evident benefits. Given the significant role of vaccination in safeguarding individual and community health, this dissertation sought to explore how the use of serious games may offer hope for addressing the COVID-19 vaccine coverage gap among youths. This dissertation collected, appraised, and synthesized existing evidence on serious game-based vaccination interventions, finding increased youths’ vaccine knowledge but limited effectiveness in boosting their vaccination intentions and uptake. Using serious game in youth health education considered key attributes including gamification, game mechanics, educational, health-related content, and objective, tailored for youth and adaptability, real life relevance, engagement, interactivity, safe environment, feedback, and assessment. Stemming from technological advances and interdisciplinary collaborations, these games provided experiences that resonated with diverse populations. Outcomes from such educational games have shown improved health knowledge, attitudes, and behaviors, improved self-efficacy and reduced health disparities. The dissertation also presented a pilot study randomization control trial (RCT) on a COVID- 19 game-based intervention (vs. usual care) targeting unvaccinated youth, showing its feasibility, acceptability and positive influence on vaccine knowledge, vaccination intention and uptake. Partnering with key stakeholders and adapting game designs for ongoing relevance could contribute to intervention effectiveness in promoting youth vaccination, catering to diverse needs and preferences.