Malaria is a serious health problem in Africa, where approximately 250 million new cases and one million deaths are recorded per year [1]. The absence of long-term prophylaxis and the emerging resistance to the current therapies highlights the necessity of new drugs for its eradication and control. Liver stage malaria parasites show an absolute requirement for type-II fatty acid biosynthesis (FAS-II) [2], rendering this pathway a good target for causal prophylaxis. In Zambia, the genus Ficus is traditionally used against malaria [3]. Hence, we collected the leaves, barks and roots of eight Zambian Ficus species and screened their crude methanol (CR-Me) extracts for in vitro activity against the multi-drug-resistant Plasmodium falciparum strain K1 using a modified [3H]-hypoxanthine incorporation assay. Malaria prophylactic potential of the extracts was also evaluated against three recombinant FAS-II elongation enzymes, FabI, FabG and FabZ, by spectrophotometric assays. All CR-Me extracts were active against P. falciparum, with F. ovata Vahl bark exhibiting the best activity (IC50 4.76µg/ml). Most of the root extracts, particularly F. sycomorus L. subsp. gnaphalocarpa (Miq.) C.C. Berg potently inhibited FabZ (96.6% inhibition at 1µg/ml). The CR-Me extracts were then subjected to solvent partitioning to yield n-hexane, CHCl3 and aq. MeOH subextracts. Remarkable antiplasmodial potency was observed in CHCl3 subextracts of four species (IC50 <2µg/ml). The leaf and root aq-MeOH subextracts were active against FabI and FabZ enzymes with inhibition rates >90% at 1µg/ml. This is the first screening of Zambian Ficus species for antimalarial potential and our results justify their traditional use.