Background: Health literacy enables a person to make good decisions regarding health care, disease prevention, and health promotion to maintain and improve health. Although health literacy research in China has gained increasing attention in recent years, most existing studies focus on adults rather than adolescents. In addition, little theory-driven empirical research has been conducted to fully understand the relationship among health literacy, its influencing factors, and health outcomes scored on a skills-based health literacy instrument. Objective: This study applied Manganello's framework to investigate how health literacy was related to its antecedents and health status in secondary students in Beijing, China. Methods: A cross-sectional study was conducted with 650 students in Years 7 to 9 (age 11-17 years) from four secondary schools. Students completed a self-administered questionnaire based on Manganello's health literacy framework, which measured key upstream determinants, including health literacy and self-report health status. Health literacy was measured on an 8-item skills-based instrument that assesses a person's ability to find, understand, appraise, and communicate health information in everyday life (scores range from 0-37). Descriptive statistics and path analysis were conducted to investigate the mediating role of health literacy in predicting health status. Key Results: Overall, the average scores of students' health literacy was 26.37 (±5.89). Manganello's framework was supported by the data collected (χ 2 /df = 2.049, p = .001, comparative fix index = 0.966, root mean square error of approximation = 0.041). Personal self-efficacy (r = 0.11, p = .007), social support (r = 0.18, p < .001), and school environment (r = 0.27, p < .001) predicted health literacy, which in turn predicted students' health status (r = 0.12, p = .005). Conclusions: Adolescent health literacy is not only a person's capability to protect health, but also an interactive outcome with the broader environment. Promoting health literacy could be a useful strategy to improve health status for adolescents; however, a holistic approach is needed to increase students' self-efficacy, promote social support, and create positive school environments to achieve optimal health literacy and health outcomes.