Tuberculosis (TB), attributable to Mycobacterium tuberculosis (M.tb), constitutes a formidable global health challenge, particularly with the proliferation of multidrug-resistant (MDR) strains. The efficacious clearance of M.tb from host cells is imperative for mitigating infection and averting disease progression. Autophagy, an intricate cellular mechanism for degrading and recycling biomolecules, plays a pivotal role in the immune response to M.tb by facilitating the degradation of intracellular pathogens through the formation of autophagosomes and their subsequent fusion with lysosomes. This study elucidates the therapeutic efficacy of DYDGP microparticles in M.tb-infected macrophages. DCFHDA staining elucidated that DYDGP significantly enhances macrophage membrane integrity and amplifies reactive oxygen species (ROS) production compared to YDGP, even in the presence of NOX-2 inhibitors. Furthermore, DYDGP promotes the biogenesis of acidic vesicular organelles and phago-lysosomal maturation, as corroborated by acridine orange and Lysotracker Red staining. Immunofluorescence and dansylcadaverine staining evidenced that DYDGP enhances autophagy induction and LC3 puncta formation in infected macrophages at both 30 min and 24 h. Protein expression analyses demonstrated elevated levels of NOX-2 and LC3, confirming autophagy induction. Antimycobacterial efficacy assessments revealed that DYDGP treatment engendered significant reductions in colony-forming units (CFUs) for H37Rv (64, 40, 19), MDR32420 (44, 35, 18), MDR32422 (44, 39, 21), and MDR32521 (38, 22, 18) at 30 min, 24 h, and 48 h, respectively. These findings accentuate DYDGP's potential to substantially attenuate M.tb burden, including in MDR strains, thereby positioning it as a promising adjunctive therapy for augmenting tuberculosis treatment.