Platycodin D (PD) is one of triterpenoid saponins isolated from the roots of Platycodon grandiflorum. In the present study, we aimed at examining the antitumor activity of PD against human hepatoma HepG2 cancer cells and investigated the underlying molecular mechanisms of PD-induced apoptosis in HepG2 cells. PD significantly inhibited the proliferation of HepG2 cells in a concentration- and time-dependent manner as assessed by MTT assay. Besides, flow cytometry revealed that PD treatment obviously induced G2/M arrest and apoptosis in HepG2 cells. Moreover, Western blot analysis demonstrated that PD induced downregulation of protein expression of PI3K, P-Akt, and Bcl-2, whereas cleaved products of caspase-3 and -9 and PARP were upregulated by PD treatment. Furthermore, the protein level of P-p38, p-38, and Bax in PD-treated HepG2 cells was kept unchanged. In addition, the inhibitors of z-DEVD-fmk (a specific caspase-3 inhibitor) and z-LEHD-fmk (a specific caspase-9 inhibitor), but not z-IETD-fmk (a specific caspase-8 inhibitor), could significantly block PD-triggered apoptosis, whereas LY294002 (Akt inhibitor) could significantly enhance PD-induced apoptosis in HepG2 cells. Thus, the increasing ratio of Bax to Bcl-2, activation of caspase-3 and -9 and PARP, and inactivation of the PI3K/Akt signaling pathway significantly enhanced PD-induced apoptosis in HepG2 cells. Our results suggest that PD induced cell cycle G2/M arrest and apoptosis in HepG2 cells by decreasing PI3K/Akt pathway. Therefore, we propose that PD has potential as a liver cancer chemotherapeutic agent.