Ent‑3α‑formylabieta‑8(14),13(15)‑dien‑16,12β‑olide (EFLDO) is a compound extracted from Euphorbia lunulata Bge exhibiting anti‑proliferative activity in vitro. In the present study, EFLDO was identified to sensitize HepG2 cells to tumor necrosis factor (TNF) superfamily member 10 (TNFSF10)‑induced apoptosis. Liver cancer cells were resistant to TNFSF10; however, EFLDO increased TNFSF10‑induced cancer cell viability inhibition and cell apoptosis induction as assessed by MTT assay and Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide assay, respectively. The western blotting results suggested that treatment with EFLDO increased TNFSF10‑induced upregulation of the protein expression levels of pro‑apoptotic proteins, including BCL2 associated agonist of cell death, BCL2 associated X, apoptosis regulator, caspase‑3 (CASP3) and CASP8. Furthermore, treatment with EFLDO increased TNFSF10‑mediated downregulation of the protein expression level of the anti‑apoptotic protein BCL2 apoptosis regulator. Notably, the increase in the activity of CASP3 was consistent with the western blotting results. Treatment with EFLDO sensitized liver cancer cells to TNFSF10, and apoptosis was induced via the upregulation of TNF receptor superfamily member 10a (TNFRSF10A) and TNFRSF10B in a tumor protein p53 (p53)‑dependent manner, as detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. In addition, p53 was identified to be necessary for EFLDO‑induced sensitivity to TNFSF10, as assessed by western blotting and Annexin V‑FITC assay. Collectively, the present results suggested a novel mechanism underlying EFLDO function in liver cancer. Treatment with EFLDO was able to increase the antitumor effect of TNFSF10 in liver cancer cells in a p53‑dependent manner.