BACKGROUND: South Africa is currently undergoing a nutrition transition, and overweight and obesity is on the increase in South African children. Urbanization and other health determinants have led to reduced physical activity and unhealthy eating that have increased the risk of adverse chronic health conditions. This study aims to provide evidence of the effectiveness of a school-based intervention study that targets diet and physical activity for the prevention of child and adolescent overweight and/or obesity. METHODS: We will employ a mixed method study design which is divided into two phases. Phase 1, namely the qualitative elicitation research phase will inform the development of the quantitative intervention phase (phase 2), consisting of a cluster-randomized trial, based on input from key stakeholders. The study will be undertaken in 16 government-funded primary schools in the iLembe district of KwaZulu-Natal, South Africa. The study will target learners in Grades 4 and 7, their parents, Life Orientation educators, school principals and members of school governing bodies. Assessment for the primary objective (BMI Z scores), and the secondary objectives (change in knowledge, attitudes and behaviours regarding diet and physical activity) in both study arms will be conducted at baseline in March 2020 and at the end of the study in October 2020. DISCUSSION: The study will be a novel combined mixed methods/RCT design that focuses on diet, physical activity school and family-based interventions in the context of rapidly increasing overweight and obesity prevalence in KwaZulu-Natal. To encourage behaviour change and management of malnutrition, education including diet and physical activity, is an important strategy that must be considered. Nutrition education extends beyond the dissemination of food information; it includes addressing the needs of participants, empowers and encourages decision-making and choice of foods, change in nutrition attitudes, beliefs and influences based on resources available and within cultural boundaries. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201711002699153. Protocol registered on 16 November 2017.