PURPOSE: The COVID-19 pandemic and subsequent lockdowns had significant impacts on the well-being of populations globally, however, most COVID-19 mental health research has been done in high-income countries. This study evaluates the impact of COVID-19 and lockdowns on the mental well-being of sequential groups of caregivers of adolescents in South Africa. We hypothesized that caregivers experienced worse mental, emotional and social health outcomes during the pandemic, compared to before its onset. METHODS: Longitudinal data from Wave 3 of the Asenze Cohort, conducted between 2019 and 2021, was used to estimate multivariable regressions to assess the association between pandemic lockdowns and caregiver social support networks, mental and physical health related quality of life, parenting stress, hazardous alcohol use, psychiatric disorder, and intimate partner violence. RESULTS: Results show that after the onset of the pandemic, caregivers experienced diminished social support networks, worse physical health related quality of life, and improvement in mental health related quality of life compared to before the pandemic. We observed no association between pandemic lockdowns with parenting stress, hazardous alcohol use, the presence of any psychiatric disorder, or experience of intimate partner violence. CONCLUSION: This study shows the impact of COVID-19 and mandated lockdowns on caregiver social support, mental and physical health related quality of life among caregivers of adolescents in South Africa. Given the results, more research is needed to discern modifiable risk factors that can be intervened on to improve social support and physical health related quality of life, and to preserve mental health related quality of life.