Dimethoxy derivatives of salicylaldehyde benzoylhydrazone containing a methoxy group on both aromatic rings were designed and synthesized. The compounds were obtained in high yields, and their structures were confirmed by elemental analysis and various spectral techniques. In vitro evaluation of dimethoxy hydrazones demonstrated potent activity against the leukemic cell lines at low micro- and nanomolar concentrations. Remarkably, two dimethoxy analogs showed exceptional antileukemic selectivity, with no toxicity observed in normal human embryonic kidney HEK-293 cells. In silico modeling identified likely interactions with the target, human cAbl kinase, and suggested a possible mechanism for their antileukemic activity.