In Nigeria, Tapinathus globiferus is used in traditional medicine in the managements of hypertension, diabetes, ulcers, infections, and skin itching, while aiding childbirth. In Europe, it addresses circulatory/respiratory issues, cancer, epilepsy, and acts as a nervous tonic. Malaria remains a devastating parasitic disease, with Plasmodium falciparum resistance to current therapies necessitating new drug targets. Plasmepsins I and II (Plm-I/II), aspartic proteases critical for hemoglobin degradation in the parasite’s life cycle, represent promising candidates. This study investigated four Tapinanthus globiferus-derived compounds—catechin (Y10), catechin-3-gallate (Y11), 4-methoxyphenyl acryl aldehyde (Y12), and 4-hydroxy-3-methoxy acryl aldehyde (Y13)—for their Plm-I (PDB: 3QS1) and Plm-II (PDB: 1LF3) inhibitory potential using molecular docking and ADMET profiling. Molecular docking revealed binding affinities ranging from −5.0 to −6.7 kcal/mol (Plm-I) and −5.6 to −8.4 kcal/mol (Plm-II). Catechin-3-gallate (Y11) exhibited the highest affinity for both enzymes (−6.7 and −8.4 kcal/mol, respectively), surpassing other ligands though lower than native co-crystallized inhibitors. Notably, Y11 formed a critical hydrogen bond with Asp214 (Plm-II catalytic dyad), explaining its enhanced binding. ADMET predictions indicated favorable drug-likeness: all compounds followed Lipinski’s rule, with catechin (Y10) classified as least toxic (Class VI). These findings highlight T. globiferus metabolites, particularly catechin-3-gallate, as promising plasmepsin inhibitors. The strong affinity and low toxicity profiles underscore their potential as antimalarial leads. Further in vitro and in vivo validation is warranted to advance their therapeutic development.