Africa is blessed with several plants and marine organisms used to treat various diseases including diabetes. The folkloric use of some of these plants in treating diabetes has been documented in various databases and publications, and validated using various diabetes models. However, most of the investigations on African medicinal plants as antidiabetic agents are not taken beyond proof-of-concept stage. Besides, limited number of clinical trials were conducted to validate the efficacy in humans and the few available clinical studies have not been critically reviewed. Therefore, this review is intended to document the antidiabetic potential of African medicinal plants investigated in human subjects as well their safety implications. Relevant articles were harvested from the major scientific databases (Scopus, PubMed, and Google Scholar). According to the present search, eighteen (18) African medicinal plants and one herbal formulation were the only plants investigated for antidiabetic activity in humans. The plants showed no noticeable toxicity throughout the study period. Interestingly, all the 18 plant species were traditionally used to treat diabetes in various parts of Africa. Despite variations in the study period and dosages used, Laportea ovalifolia (Schumach. & Thonn.) Chew. (Urticaceae) and Momordica charantia L. (Cucurbitaceae) were the most effective as they reduced fasting blood glucose by >50% after 10 days and 4 weeks treatment periods, respectively. The available information revealed that African medicinal plants especially L. ovalifolia and M. charantia should be subjected to phase III clinical trial, aimed at getting the natural product-based antidiabetic drugs from Africa.