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Through a comprehensive molecular docking study, a unique series of naphthoquinones clubbed azetidinone scaffolds was arrived with promising binding affinity to Mycobacterial Cytbc1 complex, a drug target chosen to kill multi-drug resistant Mycobacterium tuberculosis (MDR-Mtb). Five compounds from series-2, 2a, 2c, 2g, 2h , and 2j, showcased significant in vitro anti-tubercular activities against Mtb H 37 Rv and MDR clinical isolates. Further, synergistic studies of these compounds in combination with INH and RIF revealed a potent bactericidal effect of compound 2a at concentration of 0.39 μg/mL, and remaining (2c, 2g, 2h , and 2j) at 0.78 μg/mL. Exploration into the mechanism study through chemo-stress assay and proteome profiling uncovered the down-regulation of key proteins of electron-transport chain and Cytbc1 inhibition pathway. Metabolomics corroborated these proteome findings, and heightened further understanding of the underlying mechanism. Notably, in vitro and in vivo animal toxicity studies demonstrated minimal toxicity, thus underscoring the potential of these compounds as promising anti-TB agents in combination with RIF and INH. These active compounds adhered to Lipinski's Rule of Five, indicating the suitability of these compounds for drug development. Particular significance of molecules NQ02, 2a , and 2h , which have been patented (Published 202141033473). [Display omitted] • Naphthoquinones-azetidinone hybrids displayed potent anti-TB activity against H37Rv and MDR strains of Mtb. • Compound 2a showed remarkable bactericidal effect in combination with INH and RIF. • Proteomics and metabolomics studies revealed down-regulation of key proteins associated with cytbc1 complex inhibition. • The compound 2a showed minimal in vitro and in vivo toxicities, and suggests for future studies. [ABSTRACT FROM AUTHOR]