Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of extracellular protozoan parasites, namely, Trypanosoma brucei gambiense and T. brucei rhodesiense. On the other hand, Chagas disease is caused by Trypanosoma cruzi. There are currently six drugs available for the treatment of African sleeping sickness, namely, pentamidine, suramin, melarsoprol, nifurtimox, eflornithine, and fexinidazole. Besides, benznidazole and nifurtimox are drugs that are currently used for the treatment of Chagas disease. Most of the current chemotherapies for the treatment of HAT and Chagas disease are unsuitable for prescription for various reasons including high toxicity, poor efficacy, undesirable route of administration, and drug resistance. Medicinal plants are potential sources of therapeutics for many diseases. Thus, a search for compounds from plants that are active against trypanosomes could pave the way to the discovery of antitrypanosomal drugs. Therefore, the current review evaluates the potential of the secondary metabolites from medicinal plants for antitrypanosomal drug development. The literature review in the field of antitrypanosomal secondary metabolites from medicinal plants has been documented. Hence, the present study involves the discussion of antitrypanosomal natural products from medicinal plants that were not reported in these review articles present in literature. The literature search was carried out in various databases including ScienceDirect, Google Scholar, tandfonline.com, Journal of Natural Products, MDPI, WILEY Online Library, tandfonline.com, and The Lancet. In this article, the secondary metabolites organized in different classes including alkaloids, terpenoids, and flavonoids that have potency against trypanosomes are discussed.