While chronic diseases are amongst the major health burdens of older South Africans, the responsibilities of caring for grandchildren, by mostly grandmothers, may further affect older people's health and well-being. There is a paucity of information about chronic disease self-management for older people in the context of grandchildren caregiving in sub-Saharan Africa. Guided by the Self-Management Framework, the purpose of this qualitative methods study was to explore the chronic disease self-management practices and challenges of grandparent caregivers in rural KwaZulu-Natal, South Africa. Eighteen repeat in-depth interviews were carried out with six grandparent caregivers aged 56 to 80 years over 12 months. Thematic analysis was conducted based on the Self-Management Framework. Pathways into self-management of chronic illnesses were identified: living with a chronic illness, focusing on illness needs, and activating resources. Self-perceptions of caregiving dictated that grandmothers, as women, have the responsibility of caring for grandchildren when they themselves needed care, lived in poverty, and with chronic illnesses that require self-management. However, despite the hardship, the gendered role of caring for grandchildren brought meaning to the grandmothers' lives and supported self-management due to the reciprocal relationship with grandchildren, although chronic illness self-management was complicated where relationships between grandmothers and grandchildren were estranged. The study findings demonstrate that grandchildren caregiving and self-management of chronic conditions are inextricably linked. Optimal self-management of chronic diseases must be seen within a larger context that simultaneously addresses chronic diseases, while paying attention to the intersection of socio-cultural factors with self-management.