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Aspirin as an antitumor drug has been studied in various malignancies with regards to its effects on apoptosis, proliferation, metastasis and senescence of tumor cells. However, the clinical application is limited by its side effects. Nutlin‑3 is a novel antitumor compound, which has not been clinically approved. The present study investigated the value of combining aspirin and nutlin‑3 on hepatocellular carcinoma (HCC) cells. MTT was performed to detect the proliferation of HepG2 cells treated with aspirin or/and nutlin‑3. Transwell invasion assays were performed to estimate the invasion ability of HepG2 cells treated with aspirin or/and nutlin‑3. Then the apoptotic analysis of HepG2 cells evaluated the synergistic effect of aspirin and nutlin‑3. Apoptosis markers, including B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), caspase‑3, caspase‑8 and caspase‑9 were estimated by western blot analysis at various time points. In addition, a Xenograft mouse model was established by infection with HepG2 cells, and aspirin and/or nutlin‑3 was administrated to verify the anti‑apoptotic effect of the two drugs in vivo. A high dose of aspirin and nutlin‑3 inhibit the proliferation and apoptosis of HepG2 cells. The antitumor effect was enhanced with the combined treatment of the two drugs, particularly in the group with a low concentration of aspirin and nutlin‑3. Nutlin‑3 was able to increase the level of Bax in HepG2 cells treated with aspirin significantly after treatment for 8 h. When treated with a low concentration of aspirin and nutlin‑3, the level of Bax in HepG2 cells was enhanced for 2 h. In the animal model, tumor volume and tumor angiogenesis were significantly decreased in combination group compared with other groups (P<0.01). Although there were side effects in the group treated with aspirin alone, no side effects were observed in the combination group. Nutlin‑3 enhanced the apoptotic effect of a low dose of aspirin by upregulating Bax expression in the HepG2 cell line and in vivo. The synergistic effect of nutlin‑3 in aspirin antitumor therapy contributed to diminishing the dose of aspirin required and decreased the occurrence of adverse drug events in HCC through targeting the Bcl‑2/Bax signaling pathway. [ABSTRACT FROM AUTHOR]