Bioassay-directed fractionation of an antiproliferative ethanol extract of the leaves and twigs of Piptocoma antillana (Asteraceae) afforded two new goyazensolide-type sesquiterpene lactones named 5-O-methyl-5-epiisogoyazensolide (1) and 15-O-methylgoyazensolide (2), together with the known compounds 1-oxo-3,10-epoxy-8-(2-methylacryloxy)-15-acetoxygermacra-2,4,11(13)-trien-6(12)-olide (3) and 5-epiisogoyazensolide (4). The structure elucidation of all compounds was carried out based on NMR and mass spectroscopic data analyses. The relative and absolute configurations of all the isolated compounds were determined from their CD and NOESY NMR spectra. Compounds 1–4 showed moderately potent antiproliferative activities against A2780 ovarian cancer cells, with IC50 values of 1.5±0.5, 0.6±0.3, 1.62±0.05, and 1.56±0.04 µM, respectively. They also displayed antimalarial activity against Plasmodium falciparum, with IC50 values of 6.2 ± 0.5, 2.2 ± 0.5, 8.0 ±0.4, and 9.0±0.6 µM, respectively.