Informal settlements are becoming more entrenched within African cities as the urban population continues to grow. Characterised by poor housing conditions and inadequate services, informal settlements are associated with an increased risk of disease and ill-health. However, little is known about how informal settlement upgrading impacts health over time. A systematised literature review was conducted to explore existing evidence and knowledge gaps on the association between informal settlement characteristics and health and the impact of informal settlement upgrading on health, within South Africa, an upper-middle income African country. Using two databases, Web of Science and PubMed, we identified 46 relevant peer-reviewed articles published since 1998. Findings highlight a growing body of research investigating the ways in which complete physical, mental and social health are influenced by the physical housing structure, the psychosocial home environment and the features of the neighbourhood and community in the context of informal settlements. However, there is a paucity of longitudinal research investigating the temporal impact of informal settlement upgrading or housing improvements on health outcomes of these urban residents. Informal settlements pose health risks particularly to vulnerable populations such as children, the elderly, and people with suppressed immune systems, and are likely to aggravate gender-related inequalities. Due to the complex interaction between health and factors of the built environment, there is a need for further research utilising a systems approach to generate evidence that investigates the interlinked factors that longitudinally influence health in the context of informal settlement upgrading in rapidly growing cities worldwide.