Tyrosine kinase inhibitors (TKI), such as imatinib, have revolutionized chronic myeloid leukemia (CML) treatment. Despite this success, TKI intolerance and resistance remain significant clinical challenges. A promising therapeutic approach is to simultaneously target the BCR::ABL1 oncogene and other oncogenic drivers. The polycistronic miR-17-92 cluster is known to contribute to CML development and progression, but the specific roles of miR-92a-1-5p within this cluster remain unclear. In this study, we assess the roles of this microRNA and evaluate the therapeutic potential of combining microRNA inhibition with imatinib to improve treatment outcome. Our results show that miR-92a-1-5p is downregulated by imatinib in myeloid cell lines harboring BCR::ABL1 and in CML patient samples. Inhibition of miR-92a-1-5p reduces proliferation and enhances imatinib-induced cell death, while its overexpression increases proliferation and counteracts the effects of imatinib on cell death. This decrease in proliferation caused by miR-92a-1-5p inhibition is rescued after simultaneous inhibition of two newly identified target genes: BNIP3L (NIX) and TP53INP1. We confirm that miR-92a-1-5p regulates proliferation and cell cycle by targeting TP53INP1 and decreases autophagy by targeting BNIP3L. Our data suggest that miR-92a-1-5p plays a role in CML progression, and its inhibition enhances imatinib anti-leukemic efficacy, making it a potential therapeutic target.