Tuberculosis remains a major global health problem, and the emergence of drug-resistant strains of Mycobacterium tuberculosis has intensified the search for new chemical entities with potential antimycobacterial activity. In this context, benzofuran derivatives represent attractive heterocyclic scaffolds in medicinal chemistry owing to their structural versatility and broad biological relevance. Herein, we report the synthesis and preliminary in silico evaluation of a small series of ten benzofuran ester imine derivatives designed as potential antitubercular agents. The target compounds were obtained in 45–89% yields via a Schiff base condensation reaction between an amino-benzofuran ester and benzaldehyde derivatives bearing substituents with varying electronic and steric properties. Notably, the products were isolated without column chromatography, highlighting the operational simplicity of the synthetic protocol. To complement the synthetic work, the benzofuran ester imines were evaluated using PASS online to estimate their probable biological activity spectrum. The prediction suggested potential antimycobacterial activity, supporting their further analysis through structure-based computational studies. Molecular docking was subsequently performed against the ATPase domain of mycobacterial DNA gyrase B (GyrB) using the crystallographic structure from Mycobacterium smegmatis deposited in the Protein Data Bank under accession code 4B6C. In general, the docking analysis showed favorable theoretical binding energies and plausible binding modes within the active site, with non-covalent interactions that may contribute to ligand stabilization.