IntroductionComprehensive local data on adolescent health are often lacking, particularly in lower resource settings. Furthermore, there are knowledge gaps around which interventions are effective to support healthy behaviours. This study generates health information for students from cities in four middle-income countries to plan, implement and subsequently evaluate a package of interventions to improve health outcomes.Methods and analysisWe will conduct a cluster randomised controlled trial in schools in Fez, Morocco; Jaipur, India; Saint Catherine Parish, Jamaica; and Sekondi-Takoradi, Ghana. In each city, approximately 30 schools will be randomly selected and assigned to the control or intervention arm. Baseline data collection includes three components. First, a Global School Health Policies and Practices Survey (G-SHPPS) to be completed by principals of all selected schools. Second, a Global School-based Student Health Survey (GSHS) to be administered to a target sample of n=3153 13–17 years old students of randomly selected classes of these schools, including questions on alcohol, tobacco and drug use, diet, hygiene, mental health, physical activity, protective factors, sexual behaviours, violence and injury. Third, a study validating the GSHS physical activity questions against wrist-worn accelerometry in one randomly selected class in each control school (n approximately 300 students per city). Intervention schools will develop a suite of interventions using a participatory approach driven by students and involving parents/guardians, teachers and community stakeholders. Interventions will aim to change existing structures and policies at schools to positively influence students’ behaviour, using the collected data and guided by the framework forMaking Every School a Health Promoting School. Outcomes will be assessed for differential change after a 2-year follow-up.Ethics and disseminationThe study was approved by WHO’s Research Ethics Review Committee; by the Jodhpur School of Public Health’s Institutional Review Board for Jaipur, India; by the Noguchi Memorial Institute for Medical Research Institutional Review Board for Sekondi-Takoradi, Ghana; by the Ministry of Health and Wellness’ Advisory Panel on Ethics and Medico-Legal Affairs for St Catherine Parish, Jamaica, and by the Comité d’éthique pour la recherche biomédicale of the Université Mohammed V of Rabat for Fez, Morocco. Findings will be shared through open access publications and conferences.Trial registration numberNCT04963426.