Eudesmols are naturally occurring sesquiterpenoid alcohols that present cytotoxic effect to cancer cells. All eudesmol isomers displayed cytotoxicity to different tumor cell lines. α-Eudesmol showed IC50 values ranging from 5.38 ± 1.10 to 10.60 ± 1.33 μg/mL for B16-F10 and K562 cell lines, β-eudesmol showed IC50 values ranging from 16.51 ± 1.21 to 24.57 ± 2.75 μg/mL for B16-F10 and HepG2 cell lines and γ-eudesmol showed IC50 values ranging from 8.86 ± 1.27 to 15.15 ± 1.06 μg/mL for B16-F10 and K562 cell lines, respectively. In this work, we studied the mechanisms of cytotoxic action of eudesmol isomers (α-, β- and γ-eudesmol) in human hepatocellular carcinoma HepG2 cells. After 24 h incubation, HepG2 cells treated with eudesmol isomers presented typical hallmarks of apoptosis, as observed by morphological analysis in cells stained with hematoxylin-eosin and acridine orange/ethidium bromide. None of eudesmol isomers caused membrane disruption at any concentration tested. In addition, eudesmol isomers induced loss of mitochondrial membrane potential and an increase of caspase-3 activation in HepG2 cells, suggesting the induction of caspase-mediated apoptotic cell death. In conclusion, the eudesmol isomers herein investigated are able to reduce cell proliferation and to induce tumor cell death by caspase-mediated apoptosis pathways. This article is protected by copyright. All rights reserved.