Acute myeloid leukemia (AML) is a highly heterogeneous malignant clonal disease derived from hematopoietic stem cells. Although treatment strategies, such as immunotherapy, targeted therapy, and combination chemotherapy are constantly optimized and improved, the long-term survival of AML patients has not been significantly prolonged under the severe challenges of drug resistance, relapse, and disease progression. Epigenetic modifications are closely associated with the pathogenesis and progression of AML, and the regulatory mechanisms of DNA methylation, histone modification, chromatin structure remodeling, and the non-coding RNA play essential roles in the processes of gene transcription, gene expression, cell proliferation and apoptosis. With the intensive researches and clinical applications of epigenetic drugs, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, the level of individual precise treatment in AML has been significantly improved. Moreover, the combination therapies between epigenetic drugs and other anti-tumor drugs have shown great clinical application prospects, and further explorations should be strongly encouraged, as well as to provide new ideas and directions for treatments of AML patients intolerant of intensive chemotherapy and relapsed/refractory AML patients.