Schools play a crucial role in shaping the health and well-being of children and adolescents. With the global impact of COVID-19, the need for robust disease prevention and control programs within educational settings has become more apparent than ever. This study examined the association between school-based disease prevention and control programs and students' physical health and academic performance in Ghana, a developing country, with a focus on the mediating roles of mental health and health literacy. Conducted with 386 students using a descriptive cross-sectional design and a quantitative research approach, the study employed questionnaires for data collection and structural equation modeling (PLS-SEM) for analysis. The findings indicated that school-based disease prevention and control programs are associated with higher health literacy among students and linked to better physical health and academic performance. However, the impact on mental health was not significant. The results indicated that these programs are positively associated with physical health outcomes and academic achievement, with mental health serving as a partial mediator. This research highlights the importance of integrating comprehensive disease prevention and control programs, including mental health workshops, to address gaps in mental health outcomes in schools. It also emphasizes the need for governments and development partners to develop robust health policies focused on school-based health programs. Adapting these initiatives to local contexts while implementing evidence-based strategies aligns with the Sustainable Development Goals of good health and well-being (SDG 3) and quality education (SDG 4).