Refractory cancers account for therapeutic failures and tremendous financial burdens due to malignancies. The discovery of new chemotherapeutic agents preventing the growth of both drug sensitive and multidrug-resistant (MDR) cancer cell lines is an imperative necessity. This has been a research approach of several research teams in various parts of the world. In this work, we have highlighted the cytotoxic effects of a potent African plant, Vepris soyauxii, and its constituents. The geographic distribution of the plant, as well as its ethnomedicinal uses, were also provided. Twenty-seven phytochemicals were isolated from various parts of the plant, including 16 alkaloids, 7 terpenoids, and 4 phenolics. The interesting cytotoxic potential of botanicals from V. soyauxii and its constituents was reported in several human cancer cell lines, including drug-sensitive and MDR phenotypes of leukemia, breast, colon, and brain cancers. Kihadanin B (18) and soyauxinium chloride (14) were identified as the most active principle of the plant. Scientists are strongly encouraged to intensify preclinical and clinical studies on the botanicals and phytochemicals from V. soyauxii to produce novel cytotoxic drugs to combat cancers including their refractory phenotypes.