Introduction: Malaria is a major public health problem in the world, responsible for the death of millions, particularly in sub-Saharan Africa. Plasmepsins are novel targets for antimalarial drugs and are crucial to the mechanism of action by which these proteases hydrolyze peptide bonds in protein substrates. Plasmepsins I and II are the best-researched members of the aspartic protease enzyme family. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, and breakdown of host hemoglobin to release amino acids for parasite sustenance. Method: In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of quercetin, quercetrin, dihydrostilbene, 4′-methoxy-isoliquiritigenin, and stigmasterol isolated from Globimetula oreophila on plasmepsin I and II proteases. Methods include; predicting their ADME properties and molecular docking analysis. Results: Isolated compounds interacted with active site residues and sub-units, regulating protease specificity, as revealed by molecular docking. The docking analysis performed on Plasmepsin-I showed that, despite the native ligand's (lig0) lower binding energy (-9.2 Kcal/mol), compound DG4 has a better binding affinity within the binding pocket of Plm-I (-8.8 Kcal/mol). It also had the lowest binding energy of -8.8 Kcal/mol with Plm-II. The mechanism of action of these compounds revealed the existence of an aspartic protease inhibitor of plasmepsin I and II. Conclusion: Phytochemicals from G. oreophila could lead to further development of potent plasmepsin inhibitors for the prevention and treatment of malaria.