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Background Medicinal plants are regarded as a large source of phytochemicals that may have anticancer properties. This could lead to the development of innovative drugs or alternative therapy against cancer. Objective This study was designed to determine the antioxidant and cytotoxicity effect of 5 selected indigenous South African medicinal plants namely; Bulbine frutescens, Bulbine natalensis, Chlorophytum comosum, Kniphofia uvaria, and Tulbaghia violacea. Method Phytochemical extracts namely; methanol, 50%, 100% ethanol, and water extracts were prepared from the root and shoot of the plants. The antioxidant effect of methanol extracts of the plant materials was performed using a DPPH assay. A preliminary cytotoxicity screening of the phytochemical extracts in the human colon (Caco-2), cervical (HeLa), and hepatocellular (HepG2) cell lines were determined followed by the half-maximal inhibitory concentration (IC50) using MTT assay. Result The methanol root extract of B. natalensis and B. frutescens (33.20% and 26.33% respectively) and shoot extract of K. uvaria (17.10%) showed the highest antioxidant. Out of the 5 plants, only 100% ethanol extract of C. comosum, K. uvaria, and T. violacea caused more than 80% cytotoxicity in HepG2 and Caco-2 cell lines. The shoot of B. frutescens (10.43 µg/ml), K. uvaria (23.0 µg/ml), and root of C. comosum (23.77 µg/ml) were the most active with the highest cytotoxicity. Conclusion C. comosum, K. uvaria, and T. violacea possess significant cytotoxicity that is promising in developing alternative drugs against colon and liver cancers. Our results provided new pieces of evidence for antioxidant and cytotoxic activities of these plants which could be useful for developing new anticancer therapies.