Context: Anonidium mannii (Annonaceae) has been traditionally used in Africa to treat stomach aches, schistosomiasis, and many other illnesses. However, few phytochemical study and no investigation on schistosomiasis have been conducted on this species. This neglected tropical disease, caused by a worm, comes second after malaria as the most devastating parasitical infection. Aim: The goal of this study was to evaluate the anti-Schistosoma mansoni activity of fractions and constituents from A. mannii's stem bark and also to search efficient inhibitors of a recently discovered ectoenzyme of S. mansoni (S. mansoni nicotinamide adenine dinucleotide + catabolizing enzyme [SmNACE]). Materials and Methods: The powdered stem bark of A. mannii was extracted with ethanol/distilled water (80:20). The extract was then subjected to a partial bioguided separation by chromatography means. The structures of compounds were elucidated using modern spectroscopic techniques. Furthermore, isolated and semisynthetic compounds were evaluated for their antischistosomal and cytotoxic activities. Results: Chemical investigation led to the isolation and identification of eight compounds, in the majority, obtained for the first time from this genus. In addition, acetylation reactions were carried out to afford a new semisynthetic derivative. Preliminary biological screening of the extracts and compounds showed very good activities from antiparasitic and enzymatic tests and also very good percentage of cell viability evaluation. Conclusion: Like praziquantel drug, gallic acid exhibited full anthelmintic activity at concentration of 100 µM. On the other hand, piperolactam D showed important inhibition on SmNACE (IC 50 10 µM). Thus, standardization of bioactive fraction can help in improving traditional medicine. The optimization of those two compounds will enhance their selectivity/ effectiveness and could be used as seed for the development of new remedies against schistosomiasis. Further, the study will be focus on other pathogens species of Schistosoma genus.