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INTRODUCTION: Australian Aboriginal and/or Torres Strait Islander (hereafter referred to as ‘Aboriginal’) adolescents (10-24 years) experience multiple challenges to their health and well-being. However, limited evidence is available on factors influencing their health trajectories. Given the needs of this group, the young age profile of the Aboriginal population and the long-term implications of issues during adolescence, reliable longitudinal data are needed. METHODS AND ANALYSIS: The ‘Next Generation: Youth Well-being Study’ is a mixed-methods cohort study aiming to recruit 2250 Aboriginal adolescents aged 10-24 years from rural, remote and urban communities in Central Australia, Western Australia and New South Wales. The study assesses overall health and well-being and consists of two phases. During phase 1, we qualitatively explored the meaning of health and well-being for adolescents and accessibility of health services. During phase 2, participants are being recruited into a longitudinal cohort. Recruitment is occurring mainly through community networks and connections. At baseline, participants complete a comprehensive survey and undertake an extensive age relevant clinical assessment. Survey and clinical data will be linked to various databases including those relating to health services; medication; immunisation; hospitalisations and emergency department presentations; death registrations; education; child protection and corrective services. Participants will receive follow-up surveys approximately 2 years after their baseline visit. The ‘Next Generation’ study will fill important evidence gaps by providing longitudinal data on the health and social well-being of Aboriginal adolescents supplemented with narratives from participants to provide context. ETHICS AND DISSEMINATION: Ethics approvals have been sought and granted. Along with peer-reviewed publications and policy briefs, research findings will be disseminated via reports, booklets and other formats that will be most useful and informative to the participants and community organisations.