A new series of 2-(N-substituted amino)-4,5,6,7-tetrahydro benzo[b]thiophene-3-carboxylic acid ethyl ester derivatives (a–g) has been synthesized and evaluated for their anti-tubercular activity. Furthermore, all derivatives were tested for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv. Isoniazid was employed as a positive control. The minimum inhibitory concentration values of the synthesized compounds vary from 3.121 μg/ml (ic) to 100 μg/ml (ia), while the MIC values of the Isoniazid is similar to ic compound, 3.121 μg/ml. Four compounds (ic, ie, if and ig) have demonstrated more potent activity than the others and it also been validated with molecular docking simulations and ADME profile estimations. These hit compounds with better performance in both in vitro and in silico investigations, have the potential to be further investigated for the development as anti-tuberculosis agents.