Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC50s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.