Fatty acid biosynthesis is essential for bacterial survival. β-Ketoacyl–acyl carrier protein (ACP) synthase III (FabH), is a particularly attractive antibacterial target, since it is central to the initiation of fatty acid biosynthesis. Three series of 21 cinnamaldehyde acylhydrazone derivatives, A3 – 9 , B3 – 9 , and C3 – 9 , were synthesized and evaluated for FabH-inhibitory activity. Compound B6 showed the most potent biological activity against Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , and Bacillus subtilis (minimum inhibitory concentrations (MICs) values: 1.56–3.13 µg/mL) and was comparable with the positive control. Docking simulation by positioning compound B6 in the FabH structure active site was performed to explore the possible binding model.