In spite of recent reports about the presence of pharmaceuticals in African water bodies, their prevalence has still not been sufficiently quantified. The few available studies have mostly focused on a limited number of pharmaceuticals. In the present study, a suspect screening of 92 compounds (mainly pharmaceuticals and their transformation products) along the Klip River, South Africa was conducted, followed by target monitoring of 21 of the detected pharmaceuticals. The experimental approach was based on solid-phase extraction followed by analysis with ultra-high–performance liquid chromatography–quadrupole time-of-flight–mass spectrometry (UHPLC–QTOF–MS). The results revealed 47 pharmaceuticals, 31 of which were detected for the first time in South African waters. Seven detected pharmaceuticals (propyphenazole, sulfamerazine, levamisole, tryptophan, dibucaine, albuterol, and fenpropimorph) are not approved medications in South Africa. Six pharmaceutical metabolites were detected for the first time in South Africa. Pharmaceuticals with the highest concentrations in river water were flumequine (0.257 µg L−1), oxolinic acid (0.355 µg L−1), and acetaminophen (0.432 µg L−1). Oxolinic acid presented the highest hazard quotient, 48.6, indicating a risk of toxicity to aquatic organisms. Hazard quotients for other pharmaceuticals were below 1, except that of flumequine, which reached 1.285. These results suggest a need for further research into the fate of pharmaceuticals in surface waters, and a quantification of the risks associated with the identified drugs because they are likely to accumulate in the tissues of fish/aquatic organisms, thus affecting humans. Environ Toxicol Chem 2022;41:437-447.