The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.