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Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that <i>miR-15a-5p</i> was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. <i>MiR-15a-5p</i> overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which <i>miR-15a-5p</i> contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of <i>miR-15a-5p</i> decreased daunorubicin-induced autophagy. Conversely, the downregulation of <i>miR-15a-5p</i> increased daunorubicin-induced autophagy. We found that <i>miR-15a-5p</i> targeted four genes involved in autophagy, namely <i>ATG9a, ATG14, GABARAPL1</i> and <i>SMPD1</i>. Daunorubicin increased the expression of these four genes, and <i>miR-15a-5p</i> counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of <i>miR-15a-5p</i> on autophagy. In summary, our results indicated that <i>miR-15a-5p</i> induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that <i>miR-15a-5p</i> could be a promising therapeutic target for chemoresistant AML patients.