Novel Schiff bases of 2-(1-benzofuran-2-yl)quinoline-4-carboxylic acid derivatives 5a–5e were synthesized by the reaction of 2-(1-benzofuran-2-yl)quinoline-4-carbohydrazide 3 with substituted aromatic aldehydes 4a–4e in presence of catalytic amount of acetic acid. Reaction of methyl 2-(1-benzofuran-2-yl)-quinoline-4-carboxylate 2 with hydrazine hydrate upon refluxing in ethanol for 4 h gave the key intermediate, hydrazide compound 3. All newly synthesized compounds were characterized by IR, NMR and Mass spectra and screened for antibacterial and antitubercular activity. Among the tested compounds carbohydrazide 3 and the compounds 5a and 5e exhibited high activity against S. aureus and E. faecalis respectively with MIC 0.064 mg/mL. Compound 5e demonstrated significant activity against S. aureus and E. faecalis with MIC 0.064 mg/mL. The antibacterial tests revealed hydrazide derivative 3 sensitivity at 25 μg/mL, showing high activity among the synthesized compounds.