Introduction: Multidrug resistance remains a major obstacle hindering successful antimalarial chemotherapy. In the current study, 50% methanol in dichloromethane extract and six compounds from the stem bark of Zanthoxylum gilletii were explored for their antiplasmodial potential against three strains of Plasmodium falciparum. Materials and Methods: The extract was obtained by cold percolation using 50 % MeOH in CH 2 Cl 2 and the antiplasmodial activities were assayed using a non-radioactive Malaria SYBR Green I assay to determine a concentration that inhibits growth of 50% of parasites in culture (IC 50 ). Results and Discussion: Chromatographic separation of the crude extract yielded six known compounds including: one lignan, sesamin (1), an alkamide, fagaramide (2), three benzo [c] phenanthridine alkaloids, 8-acetonyldihydrochelerythrine (3), dihydrochelerythine (4), norchelerythrine (5) and one pentacyclic triterpenoid, lupeol (6). The extract and sesamin (1) showed promising antiplasmodial activities against the chloroquine resistant (W2), chloroquine sensitive (D6) and 3D7 strains of P. falciparum, with IC 50 values of 2.52, 1.48 and 1.43 µg/mL and 5.4, 9.1 and 8.3 µM, respectively. To the best of our knowledge, this is the first report on antiplasmodial activities of the stem bark extract (50%