Several promising compounds against multi-drug-resistant Mycobacterium tuberculosis (MTB) are currently in the drug discovery and development pipeline. While it has yet to establish candidature in this pipeline, early results have been promising for the putative anti-mycobacterial potency of the indolizine scaffold. The molecular properties, as well as the Absorption, Disruption, Metabolism, Excretion and Toxicity (ADMET) of indolizines were assessed using the Accelry's Discovery Studio 4.0 client package. The current study evaluated the in vitro potency of 14 diversely substituted indolizine congeners against H37Rv and multi-drug-resistant strains of M. tuberculosis. While all 14 congeners showed potent anti-mycobacterial activity, only three of them had optimal drug-likeness and toxicology, as per in silico evaluations. The results of the current study identify three indolizine congeners (ethyl 2-methyl-3-(4-methylbenzoyl) indolizine-1-carboxylate (1b)), ethyl 7-acetyl-3-benzoyl-2-methylindolizine-1-carboxylate (3a) and ethyl 7-acetyl-3-benzoyl-2-ethylindolizine-1-carboxylate (3b) with good anti-mycobacterial potency and acceptable drug-likeness and toxicity profiles. Furthermore, the study narrows down the list of indolizine congeners for further evaluation and underscores the importance of computational tools in mitigating the over-utilization of resources and associated costs of drug discovery.