Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematologic malignancy whose pathogenesis and progression are influenced by a variety of molecular mechanisms. These encompass genetic mutations, aberrant signaling pathways, epigenetic dysregulation, and complex interactions within the tumor microenvironment. Hypoxia-inducible factor- 1α (HIF-1α), a master regulator of cellular response to low oxygen tension, is frequently overexpressed in AML, and its abnormal expression is closely associated with poor patient prognosis. The histone methyltransferase enhancer of zeste homolog 2(EZH2), recognized as a high-risk molecular marker in the Chinese adult AML diagnosis and treatment guidelines, exhibits a context-dependent dual regulatory role. It can lose its tumor-suppressive function through loss-of-function mutations, while in specific disease stages, its overexpression contributes to maintaining leukemia stem cell properties and mediating chemotherapy resistance. Research indicates that HIF- 1α and EZH2 may engage in synergistic crosstalk in AML, potentially forming a "metabolism-epigenetics" axis. This interaction creates a positive feedback loop that cooperatively promotes leukemia cell proliferation, blocks differentiation, facilitates metabolic reprogramming, and aids in immune evasion. This article provides a comprehensive review of the expression patterns, biological functions, interaction mechanisms, and clinical translational potential of HIF-1α and EZH2 in AML. The aim is to offer a theoretical foundation and suggest research directions for a deeper understanding of AML pathogenesis and the development of novel combination targeted therapy strategies.