INTRODUCTION: Globally, no person has been untouched by the COVID-19 pandemic. Yet, little attention has been given to children and adolescents in policy, provision and services. Moreover, there is a dearth of knowledge regarding the impact of COVID-19-associated orphanhood and caregiver loss on children. This study aims to provide early insights into the mental health and well-being of children and adolescents experiencing orphanhood or caregiver loss in South Africa. METHODS AND ANALYSIS: Data will be drawn from a quantitative longitudinal study in Cape Town, South Africa. A sample of children and adolescents between the ages of 9 and 18 years, experiencing parental or caregiver loss from COVID-19, will be recruited together with a comparison group of children in similar environments who did not experience loss. The study aims to recruit 500 children in both groups. Mental health and well-being among children will be explored through the use of validated and study-specific measures. Participants will be interviewed at two time points, with follow-up data being collected 12-18 months after baseline. A combination of analytical techniques (including descriptive statistics, regression modelling and structural equation modelling) will be used to understand the experience and inform future policy and service provision. ETHICS AND DISSEMINATION: This study received ethical approval from the Health Research Ethics Committee at Stellenbosch University (N 22/04/040). Results will be disseminated via academic and policy publications, as well as national and international presentations including high-level meetings with technical experts. Findings will also be disseminated at a community level via various platforms
