Although imatinib has revolutionized the treatment of chronic myeloid leukemia (CML), s develop resistance to imatinib when progress to blast phase and relapse. Myricetin, a flavonoid compound found in natural plants, has multiple biological functions. In this study, we show that myricetin demonstrated potent efficacy in imatinib-resistant CML CD34+ stem/progenitor cells with less toxicity in normal bone marrow. Myricetin is also active against imatinib-resistant CML bulk cells. The in vitro observations on the therapeutic effects of myricetin were translatable to in vivo imatinib-resistant CML xenograft mouse models. Mechanism studies showed that myricetin decreased the phosphorylation of eIF4E and Ak strain transforming, and the protein level of c-Myc and Cyclin D1. Rescue studies using eIF4E (S209D) and (S209A) confirmed that eIF4E phosphorylation inhibition was the mechanism of myricetin’s action in CML. Our results suggest that myricetin may be a potential lead for drug development to overcome imatinib resistance in CML.