Purpose: Epigenetic gene silencing due to promoter hypermethylation& histone acetylation influence various molecular pathways in leukemogenesity of Acute Myeloid Leukemia (AML). Combined use of DNA methyltransferases & histone deacetylases inhibitors proved to reverse the methylomic phenotype of myeloid blasts & improve patient's prognosis. The study recruited 68 Adults patients 45 received novel combination of the HDACi valproic acid +/- the Dnmt1 inhibitor; epigallocatechingallate “EGCG" parallel to standard chemotherapy for 2 successive cycles. Results: We recorded; 37/45 (CR), 7 (PR) &1 (RF), 60% MRD elimination. Decreased Dnmt1 & HDAC1 activities (p<0.001). Reversed P15^INK4B gene methylation & expression states 58 %, (p<0.02) & decreased levels of VEGF, bfgf, IL-6, NF-KB, TNF, COX-2 & P65 cytokines levels in a harmonized orchestra (p<0.01). Survival analyses showed high significant 2 years DFS (P<0.01). Conclusion: The used epi-drug combination distinctively exerted a destructive impact on AML blasts interpreted to tumor regression, better hematological & clinical response.