Abstract: Acute myeloid leukemia (AML) is a clonal malignant disease of hematopoietic stem cells, associated with suboptimal responses to conventional therapy, particularly in elderly patients and those unfit for intensive chemotherapy, who experience poorer outcomes. Venetoclax, a highly selective BCL-2 inhibitor, exerts its antileukemic effect by inducing tumor cell apoptosis. In recent years, significant progress has been made in the treatment of AML using Venetoclax in combination with epigenetic drugs. Epigenetic drugs, such as DNA methyltransferase inhibitors (e. g., azacitidine and decitabine) and histone deacetylase inhibitors, can regulate gene expression and restore normal cell differentiation. The combination of venetoclax and epigenetic agents shows marked synergistic efficacy, remodeling the epigenetic landscape of leukemia cells and sensitizing them to apoptosis. Early clinical trials have confirmed that this combination can improve the remission rate and prolong the survival of AML patients.This review aims to describe the synergistic mechanisms and clinical research progress of epigenetic drugs in combination with Venetoclax for the treatment of acute myeloid leukemia, providing references for clinical practice and further research.