There has been a notable increase in the use of ethnomedicines in developing nations, primarily due to their low cost, widespread availability, and the belief that they are safer alternatives to conventional medicines. Portulacaria afra (P. afra), a medicinal plant native to South Africa, has been traditionally used in treating diseases such as diabetes, diarrhoea, fever, hypertension, and various skin and blood disorders. This review examines the pharmaceutical potential of P. afra, focusing on its bioactive compounds, pharmacological uses, and therapeutic potential. Various approaches were used to gather relevant data, including searches through databases such as Google Scholar, PubMed, and ScienceDirect. In vitro studies have demonstrated multiple biological activities, including antioxidant, anti-inflammatory, anti-diabetic, anti-bacterial, and cytotoxic effects. Phytochemical analysis has identified groups of compounds in P. afra, such as flavonoids, phenolic acids, alkaloids, saponins, tannins, and glycosides. Bioactive compounds such as lupeol and piperidine have also been identified recently. However, a major limitation is that these pharmacological findings are confined to in vitro studies, with little or no significant in vivo studies to validate these effects. Hence, further research is essential to assess the pharmacological activities in vivo, clinical efficacy, safety of P. afra, and the therapeutic mechanism(s) to understand its folkloric use as a possible candidate in modern therapeutics.