Tuberculosis (TB) is one of the world's deadliest infectious diseases, caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). In the present study, a 3D QSAR study was performed for the design of novel substituted benzimidazole derivatives as anti-mycobacterial agents. The anti-tubercular activity of the designed compounds was predicted using the generated 3D QSAR models. The designed compounds which showed better activity were synthesized as 1,2-disubstituted benzimidazole-5-carboxylic acid derivatives (series 1) and 3-substituted-5<i>H</i>-benzimidazo[1,2-<i>d</i>][1,4]benzodiazepin-6(7<i>H</i>)-one derivatives (series 2) using the liquid phase combinatorial approach using a soluble polymer assisted support (PEG5000). The compounds were characterized by <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, FTIR and mass spectrometry. HPLC analysis was carried out to evaluate the purity of the compounds. We observed that the synthesised compounds inhibited the growth of intracellular <i>M. tuberculosis</i> H<sub>37</sub>Rv in a bactericidal manner. The most active compound <b>16</b> displayed an MIC value of 0.0975 μM against the <i>Mtb</i> H<sub>37</sub>Rv strain in liquid cultures. The lead compound was also able to inhibit the growth of intracellular mycobacteria in THP-1 macrophages.