From a biopsychosocial perspective, health literacy is a key factor for healthy development and the development of more comprehensive interventions directed at health literacy determinants. The present study had the main goal of studying demographic, individual, social, and contextual variables related to health literacy in adolescents. The data used in this study are part of the Health Behavior in School-aged Children (HBSC) 2022 survey. The study included 7649 adolescents, 53.9% (n = 3961) female, with an average age of 15.05 years (SD = 2.36), in the 6th, 8th, 10th, and 12th grades, proportionally distributed across the five regions of the Portuguese mainland. Health literacy was explained by factors related to physical, psychological, social, and environmental health. The factors with the higher explanatory value were the psychological variables, followed by social and lifestyle-related variables. Sociodemographic and environmental factors had a more modest explanatory value. These results point to the complexity of adolescents' health literacy. These results are of the utmost importance for educators, professionals, and policymakers who can use this information to create friendly environments that promote health literacy and health-promoting activities according to a multidisciplinary, continuous, and consistent plan.