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In this study, a series of novel quinolinone-based thiosemicarbazones were designed in silico and their activities tested in vitro against <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>). Quantitative structure-activity relationship (QSAR) studies were performed using quinolinone and thiosemicarbazide as pharmacophoric nuclei; the best model showed statistical parameters of R² = 0.83; F = 47.96; s = 0.31, and was validated by several different methods. The van der Waals volume, electron density, and electronegativity model results suggested a pivotal role in antituberculosis (anti-TB) activity. Subsequently, from this model a new series of quinolinone-thiosemicarbazone <b>11a</b>–<b>e</b> was designed and docked against two tuberculosis protein targets: enoyl-acyl carrier protein reductase (InhA) and decaprenylphosphoryl-<i>β</i>-<i>D</i>-ribose-2’-oxidase (DprE1). Molecular dynamics simulation over 200 ns showed a binding energy of −71.3 to −12.7 Kcal/mol, suggesting likely inhibition. In vitro antimycobacterial activity of quinolinone-thiosemicarbazone for <b>11a</b>–<b>e</b> was evaluated against <i>M. bovis</i>, <i>M. tuberculosis</i> H37Rv, and six different strains of drug-resistant <i>M. tuberculosis</i>. All compounds exhibited good to excellent activity against all the families of <i>M. tuberculosis</i>. Several of the here synthesized compounds were more effective than the standard drugs (isoniazid, oxafloxacin), <b>11d</b> and <b>11e</b> being the most active products. The results suggest that these compounds may contribute as lead compounds in the research of new potential antimycobacterial agents.