Abstract <p><b>Objective:</b> The molecular structure of quinoline–pyridine hybrids suggests their potential as therapeutic agents, particularly for the treatment of tuberculosis, due to their notable biological activity. In light of the increasing prevalence of drug-resistant strains of <i>Mycobacterium tuberculosis</i>, our research focuses on the development of novel compounds with enhanced antitubercular efficacy. <b>Methods:</b> As part of our ongoing efforts to identify effective antitubercular agents, we synthesized quinoline–pyridine hybrids <i>via</i> a one-pot Mannich reaction, employing 3-aminoquinoline, aryl aldehydes, and 3-acetylpyridine in the presence of zirconium(IV) chloride (ZrCl₄) as a catalyst. Various Lewis acids, Brønsted acids, and organocatalysts were evaluated to optimize the yield of the target compounds. The synthesized molecules were characterized using ¹H, ¹³C NMR, IR, and mass spectrometry. <b>Results and Discussion:</b> Among the synthesized compounds, (<b>IVb</b>) (bearing a 2-chloro substituent), (<b>IVf</b>) (with 2,4-dichloro substituents), and (<b>IVg</b>) (bearing a 4-nitro group) exhibited moderate antitubercular activity, with minimum inhibitory concentrations (MIC) of 12.5 µg/mL against <i>M. tuberculosis</i> H37Rv. These compounds showed promising efficacy in comparison to standard antitubercular drugs such as isoniazid, rifampicin, and ethambutol. The findings indicate that the presence of electron-withdrawing groups, such as chloro and nitro substituents, enhances the compounds’ activity against the pathogen. <b>Conclusions:</b> The quinoline–pyridine Mannich bases synthesized in this study represent a promising scaffold for the development of novel antitubercular agents. The increased efficacy of selected derivatives highlights their potential for further development as therapeutic candidates in tuberculosis treatment.</p>