A series of vanillin derivatives have been designed and synthesized and their biological activities were also evaluated as potential inhibitors of FtsZ. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their FtsZ inhibitory activity. Compound 4u showed the most potent antibacterial activity with MIC of 0.28 μg/mL against E. coli strains and exhibited the most potent FtsZ inhibitory activity with polymerization IC50 of 2.1 μM. Docking simulation was performed to position compound 4u into the FtsZ active site to determine the probable binding conformation.