Refractory acute myeloid leukemia (AML) remains a challenging hematological malignancy to treat, due to the development of drug resistance, severe complications, and relapse in chemotherapies. Free-drugs combination has demonstrated enhanced therapeutic efficacy in AML, while it requires complicated administration regimes and brings added toxicity. To tackle this complex disease, in this work two clinically applied therapeutics, doxorubicin and homoharringtonine, were assembled into one polymeric micelle to form a co-delivery system (DHM) to facilitate a novel and simple administration regimen. The DHM was systematically investigated in the drug-resistant AML cell line HL60/A as well as in the AML1-ETO-c-kit mouse featuring as a refractory and relapsed AML model following comprehensive characterizations. Compared with the free-drugs combination, DHM significantly enhanced the cellular uptake of the therapeutics, inhibited the cell division and induced a higher rate of cells apoptosis in vitro. More importantly, the intraperitoneal injection of DHM remarkably eradicated leukemia cells in the peripheral blood, bone marrow, spleen and liver of the AML mice and significantly prolonged the survival of the mice without additional systematic toxicity compared with that of the free drugs combination. In conclusion, the DHM boosted the therapeutic effect of clinically applied chemodrugs as well as provided a novel platform for multi-drugs co-delivery against refractory and relapsed AML, therefore holding promising potential for translational medicine.Copyright © 2020. Published by Elsevier B.V.