While adolescent health literacy has gained momentum, it is under-researched from a cross-cultural perspective. This study aims to compare health literacy among two cultural groups of secondary students in Beijing and Melbourne. A cross-sectional study was conducted with 770 students from five secondary schools in Beijing and Melbourne. A self-administered questionnaire was designed to collect information on health literacy (the eight-item health literacy assessment tool (HLAT-8), the Newest Vital Sign (NVS) and the 47-item Health Literacy Survey (HLS-47)), its antecedents and health outcomes. Overall, students’ health literacy in Melbourne (n = 120) was higher than that in Beijing (n = 650): 28.25 ± 6.00 versus 26.37 ± 5.89 (HLAT-8); and 4.13 ± 1.73 versus 3.65 ± 1.64 (NVS). The proportion of students with low health literacy varied by instruments, representing 23.7–32.2% in Melbourne and 29.0%–45.5% in Beijing. In both cultural groups, students’ self-efficacy, social support, and perceptions of school environment were associated with their health literacy, which in turn predicted their health behaviours, patient-provider communication and health status. Given the nature of our study design and small samples, a cautious conclusion would be that adolescent health literacy is sensitive to the broad cultural context and might be an interactive outcome influenced by an individual’s health skills and the social environment. Particularly, creating a supportive school environment is critical to develop adolescent health literacy that would eventually contribute to better health outcomes.