Background: In the 21st century, grandparenthood is a significant phenomenon in the fields of demography, gerontology and sociology. It is mainly explored in the context of ageing, as it is poised to become one of the most significant demographic phenomena and social issues in contemporary South Africa. Therefore, this study examined the determinants associated with grandparents who are parenting as caregivers and the health challenges they are exposed to as a caregiver. Methods: The National Income Dynamics Study (NIDS) Wave 5 dataset was utilized, and a total of 302 476 grandparents aged 25 years and older, who reported to be primary caregivers of double orphans, were included in the analysis. Both bivariate and multivariate binary logistics regression were performed to determine the predictors of the determinants of grandparents parenting as a caregiver and their health challenges in South Africa. Estimated odds ratios (ORs) with 95% confidence intervals (CIs) were used, and the threshold for statistical significance was established at ?< 0.05. Results: A majority of the male and female grandparent caregivers are aged 24-34 years, were black Africans (69.8%), had secondary education (46.9%), reported health challenges (HC) (59.7%), with 26.4% reporting headaches in the last 30 days. Logistic regression revealed that grandparent caregivers aged 55-64 years were 8.9 times more likely to report health challenges as compared to those aged 25-34 years. Non-black African grandparent caregivers were found to be 0.61 times less likely to be report health challenges, compared to Black African grandparent caregivers. Those with perceived poor health status were 3.3 times more likely to report health challenges, compared to those with excellent perceived health status. Conclusion: Therefore, there is an urgent need to redesign health interventions to address these health burdens among grandparent caregivers and to take cognizance of providing economic and social support for these vulnerable populations.