Climate change threatens the health and well-being of populations. We conducted a risk assessment of two climate-related variables (i.e., temperature and rainfall) and associated water, sanitation and hygiene (WASH)-related exposures and vulnerabilities for people living in Mopani District, Limpopo province, South Africa. Primary and secondary data were applied in a qualitative and quantitative assessment to generate classifications of risk (i.e., low, medium, or high) for components of hazard/threat, human exposure, and human vulnerability. Climate-related threats were likely to impact human health due to the relatively high risk of waterborne diseases and WASH-associated pathogens. Vulnerabilities that increased the susceptibility of the population to these adverse outcomes included environmental, human, physical infrastructure, and political and institutional elements. People of low socio-economic status were found to be least likely to cope with changes in these hazards. By identifying and assessing the risk to sanitation services and water supply, evidence exists to inform actions of government and WASH sector partners. This evidence should also be used to guide disaster risk reduction, and climate change and human health adaptation planning.