This study examined the mechanisms underlying the interactions between the natural polyphenol Resveratrol and HDAC inhibitors in both U937 myelomonocytic leukemia cell line and blood samples from AML patients and normal cord blood. Simultaneous exposure to Resveratrol and HDAC inhibitors (Vorinostat-SAHA or Panobinostat-LBH589) resulted in potentiating the lethality caused by any single agent of the combination, this interaction found to be synergistic at multiple concentrations. Exposing U937 cells to minimal toxic doses of Resveratrol and HDACIs results in release of mitochondrial pro-apoptotic proteins AIF and cytochrome c, pro-apoptotic caspase activation especially caspase-8, and induction of DNA damage. These events were associated with increase deacetylation of NF-κB and reactive oxygen species generation, as well as G0-G1 cell cycle arrest. Genetic knockdown of SIRT1 (a deacetylator of NF-κB that is upregulated by Resveratrol) resulted in significant increase in NF-κB acetylation and activity. However, SIRT1 knock down failed to protect U937 cells against combination-induced cell death, implying the possibility of the involvement of other mechanisms in inducing cell death rather than NF-κB deactivation only. Co-incubation of the antioxidant vi MnTBAP significantly reduced Resveratrol/HDACIs induced cell death, and resulted in a marked decrease in caspase-8, caspase-3, and PARP activation. Finally, the combined treatment of Resveratrol/HDACIs induce cell cycle changes possibly through Resveratrol action of blocking cell cycle in S phase exposing more cells to HDACIs lethality. Collectively, these finding indicate that the combined regimen of Resveratrol and HDAC inhibitors promote lethality in U937 cells and primary AML cells by a variety of mechanisms. The approved use of both agents in clinical setting make future clinical studies for development of this drug regimen a potential option in the battle with leukemia.