Cussonia spicata is an evergreen tree widely used as herbal medicine throughout its distributional range in tropical Africa. The current study is aimed at providing a critical review of the phytochemistry, pharmacology, and evaluation of the medicinal potential of C. spicata. Documented information on the phytochemistry, pharmacology, and medicinal applications of C. spicata was collected from several online sources which included BMC, Scopus, SciFinder, Google Scholar, Science Direct, Elsevier, PubMed, and Web of Science. Additional information on the phytochemistry, pharmacology, and medicinal applications of C. spicata was gathered from pre-electronic sources such as book chapters, books, journal articles, and scientific publications sourced from the University library. This study showed that the bark, flowers, flower stalks, fruits, leaves, roots, root bark, and stems of C. spicata are used as antifebrile and emetic and herbal medicine for fever, nausea, vomiting, gonorrhea, venereal diseases, malaria, and mental illness. Phytochemical compounds identified from the leaves, root bark, stems, and stem bark of C. spicata include alkaloids, anthocyanins, anthracene glycosides, botulin, condensed tannins, free gallic acid, gallotannins, iridoids, pentacyclic triterpenoids, saponins, steroids, tannins, flavonoids, phenolics, triterpenoids, and volatile oils. Pharmacological research revealed that C. spicata crude extracts and compounds have acetylcholinesterase, antibacterial, antiviral, anti-inflammatory, antileishmanial, antiplasmodial, antiprotozoan, antioxidant, larvicidal, molluscicidal, spermicidal, and cytotoxicity activities. Future research should focus on evaluating the phytochemical, pharmacological, and toxicological properties of C. spicata crude extracts as well as compounds isolated from the species.