The focus of this review article was to outline the sources, pathways, effects, occurrence, and spatial distribution of the most prescribed pharmaceuticals in wastewater and receiving waters of South Africa. Google Scholar, Web of Science, and Scopus were used to gather data from different regions. A zone-wise classification method was used to determine the spatial distribution and data deficiencies in different regions of South Africa. This review revealed that over 100 pharmaceutical compounds have been reported in South Africa’s various water sources and wastewater, with most studies and highest concentrations being documented in Gauteng and Kwa-Zulu Natal. The pharmaceutical concentration in water samples ranged from ng/L to µg/L. Aspirin, ketoprofen, diclofenac, ibuprofen, naproxen, erythromycin, tetracycline, sulfamethoxazole, acetaminophen, streptomycin, ciprofloxacin, ampicillin, carbamazepine, atenolol, pindolol, efavirenz, and zidovudine residues were among the frequently detected pharmaceutical residues in water bodies and wastewaters of South Africa. Based on the spatial distribution data, Gauteng has the highest number of pharmaceuticals (108) detected in waste and surface water, with the Northern Cape having no monitoring evidence. Therefore, to precisely ascertain the geographical distribution of pharmaceutical contaminants in South Africa, this review recommends that further research be carried out to track their occurrence in aquatic environments and WWTP, especially in isolated regions like Limpopo.