From the crude ethanol extract of Wedelia trilobata leaves, hexane and dichloromethane fractions exhibited in vitro antimalarial activity against the Plasmodium falciparum parasite (strain PFB), with IC50 values of 27.0 and 13.0μg/mL, respectively. Specifically, two new (9R)-eudesman-9,12-olide δ-lactones, wedelolide G (1) and wedelolide H (2), were isolated from the dichloromethane extract and showed IC50 values of 3.42 and 5.96μM, respectively. Six known compounds are also present in the extract. The structures of 18 were elucidated through spectroscopic studies.