Gigantol is a phenolic substance extracted from plants in the genus Dendrobium and used in traditional Chinese medicine. In the present study, we aimed to investigate the growth inhibition and apoptotic effects of gigantol on human liver cancer cells through the PI3K/Akt/NF-κB signaling pathway. HepG2 cells were treated with different concentrations of gigantol (0-150 µM) for 12, 24 and 48 h. It was found that gigantol significantly inhibited the proliferation and induced apoptosis of the HepG2 cells. The results of fluorescence micrographs showed that a 48-h treatment with gigantol induced typical apoptotic morphological features, which were consistent with the flow cytometric analysis where 20% of apoptotic cells were detected in response to gigantol treatment. In addition, western blot analysis indicated that gigantol enhanced the activities of caspase-3, PARP and p53 and downregulated the expression of p-Akt/Akt. Collectively, the present data suggest that gigantol induces growth inhibition and apoptosis of HepG2 cells via the PI3K/Akt/NF-κB signaling pathway.