The Combretum genus belongs to the family Combretaceae. It consists of about 370 species of herbs, shrubs, and trees widely used by African traditional healers due to their efficacy in controlling different maladies. Some of the species have gained recognition in the pharmacopeia as drugs and herbal teas, both within Africa and beyond. The phytochemical and biological study of the genus is gradually expanding and has generated several evidence-based platforms for further studies and the development of useful phytopharmaceuticals. This review critically assesses flavonoids, which are the second-largest phytochemical class of compounds in the genus. Different search engines, including Google Scholar, Google, SciFinder, PubMed, ScienceDirect, and printed books, were employed with different search terms. Trends, structural patterns, biological activities, and several limitations within the genus have been discovered for further research follow-ups regarding eight nine (89) flavonoids (flavanols, flavans, flavanones, chalcones, anthocyanins, and flavones) isolated from the genus between 1990 and May 2022. The isolated flavonoids exhibited antidiabetic, anthelmintic, antimicrobial, antioxidant, antimalarial, and anticancer activities. Particularly, phosphoenolpyruvate carboxykinase (PEPCK) gene inhibitor, (−)-epicatechin (27) from Kinkeliba; the antioxidant compounds, velutin (57), belamcanidin (58), and cirsilineol (59) from C. fragrans and the anticancer effects of 3-O-(-L-rhamnopyranosyl)-3′,4′,5′,5,7-pentahydroxyflavone (78), and myricetin-3-O-glucoside (77) from C. platypetalum, are significant discoveries for further investigation of their therapeutic mechanisms of action and other preclinical protocols. Based on the scientific data generated from the genus and the traditional uses, evidence-based development of possible natural drug candidates should form the focus of future investigations.

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