Single‑agent histone deacetylase (HDAC) inhibitors have exhibited marked antileukemic activity in preclinical and clinical studies and have undergone trials in combination with standard chemotherapeutics. However, the mechanisms of action of combination therapies are not completely understood. In the present study, a novel strategy for treatment of acute myeloid leukemia (AML) was identified, in which the chemotherapeutic agent, homoharringtonine (HHT), was combined with suberoylanilide hydroxamic acid (SAHA), a pan‑HDAC inhibitor. A synergistic effect was observed when HHT was added to SAHA to induce apoptosis in Kasumi‑1 and THP‑1 leukemia cells. This combination was found to significantly enhance the activation of caspase‑8 and ‑9 compared with treatment with each drug separately. Notably, while SAHA induced upregulation of death receptor 4 (DR4) and DR5, HHT upregulated tumor necrosis factor‑related apoptosis-inducing ligand (TRAIL) expression in a dose‑dependent manner. In addition, the synergistic effect between HHT and SAHA was blocked partially using a specific anti‑TRAIL antibody. The combination therapy was also found to significantly inhibit the growth of leukemia xenografts in vivo with enhanced apoptosis. These results indicate that, by regulating the induction of TRAIL and activation of the TRAIL apoptotic pathway, it is possible to administer HHT at low concentrations in combination with SAHA as an effective therapeutic approach for the treatment of AML.