Schools provide conducive environments for disseminating messages on health by implementing appropriate learning approaches and subjects such as biology in the curriculum. For instance, problem-based learning (PBL) is a student-centred approach commonly applied in the field of education. However, its implementation to improve the health literacy of secondary school students is a challenge. This study analyzes the perceptions of problem-based learning and its influence on health literacy in secondary school students. Lessons in biology are chosen as a platform for health literacy development since they cover topics related to disease and health. Quasi-experimental studies show that problem-based learning improves biological knowledge and health literacy. This study shows that students' perceptions of the problem-based approach were empirically related to increased health literacy. These results provided the empirical and theoretical background for the application of problem-based learning in biology classes.