In the field of medicinal chemistry, benzimidazole is a useful pharmacophore and shows a broad range of biological activities. Modern drug development commonly use the molecular docking technique for understanding drug-receptor interaction. Various computational techniques, including 2D QSAR, molecular docking, and ADME studies of benzimidazole derivatives against Escherichia Coli and Staphylococcus aureus, were used in this research study. Molecular descriptors used in 2D QSAR studies, include topological index Balaban (J), electronic parameters like Vamp Lumo & Kier's second order alpha shape index (kα2) against Escherichia Coli microorganism. The antibacterial activity of benzimidazole derivatives is governed by topological parameters like third-order molecular connectivity index (3χ) against Staphylococcus aureus microorganism. According to molecular docking studies, compounds 15, 2, 4, 7 and 24 have the best docking scores against the protein Topoisomerase II (PDB ID: 1JIJ) and compounds 14, 27, 2, 25 and 15 have the best docking scores against the protein DNA Gyrase (PDB ID: 1KZN). The Lipinski rule of five was used to determine an excellent ADME profile based on QSAR, molecular docking data, and binding interaction analysis. According to the study, these compounds may be used as lead structures for more investigation of antimicrobial resistance.