Diarrhea is a common cause of child-related hospitalization and mortality among children under the age of five in South Africa. This study was conducted to assess the knowledge and practices of caregivers regarding prevention and management of diarrhea among children under the age of five in the Thulamela Municipality of South Africa. A quantitative approach using a descriptive cross-sectional survey was used. A questionnaire was adopted to collect data from caregivers at thirty primary health-care facilities using convenient sampling. Statistical Package for Social Sciences (SPSS) version 24.0 was used to analyze data. Most of the respondents have fair knowledge about diarrhea, oral rehydration therapy/salt sugar solution and its usage during diarrheal episodes. However, most of them (81.7%) do not use the salt sugar solution when their children have diarrhea. Almost all the respondents practice a hand washing hygiene for themselves and their children; 97.2% do not reheat cooked food before feeding their children; 95.5% do not drink untreated water as their source of drinking water is the municipal supply. The practices of these respondents do not reflect their knowledge in terms of the use of oral rehydration solution/salt and sugar solution. Further efforts should be made to educate caregivers on the mode of transmission of diarrheal pathogens.