Background: Amidst the COVID-19 pandemic, the proliferation of fake news and an infodemic has highlighted the necessity to enhance health literacy, particularly among school-aged children in the concrete operational phase of cognitive development. However, current health literacy studies predominantly focus on the adult population and overlook COVID-19 prevention protocols. Objective: This study aimed to evaluate the effectiveness of COVID-19 prevention education utilizing interactive comic and animated videos on the health literacy of school-aged children in Sleman Regency, Yogyakarta, Indonesia. Methods: The study employed a quasi-experimental research design with pretest-posttest nonequivalent control groups conducted from July to November 2021. Non-random sampling was utilized to select elementary schools and students, resulting in seventy-eight respondents. Health literacy was assessed using the modified 22-item Indonesian version of the Health Literacy Scale of COVID-19. Data analysis employed the Wilcoxon test. Results: Significant improvements in children’s health literacy were evident within the intervention group from pretest to posttest (p = 0.046, p <0.05). Conversely, no significant change was observed within the control group post-intervention. Furthermore, comparable pre-intervention health literacy levels were noted across both groups, with a modest increase post-intervention, suggesting the intervention’s potential to enhance health literacy, albeit to a limited extent. Conclusion: The research highlights the significance of focused health education for school children, particularly in preventing COVID-19. Incorporating interactive media such as animated videos and comics in school programs can improve health literacy. Policymakers need to invest in creating and sharing engaging health education materials working with schools, communities, and parents. Moreover, integrating artificial intelligence-driven personalized learning platforms may be possible to enhance information delivery, enabling children to confidently address health issues in the digital era. These findings may also guide post-pandemic health education approaches, ensuring children are informed and ready for future health challenges.