Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), has been a major source of human suffering since antiquity. Presently, over 2 billion people are infected by M.tb worldwide, leading to an estimated 10 million active TB cases and 1.4 million deaths in 2020. Drug-resistant TB is becoming a major threat in the global TB control. Multidrug-resistant/rifampicin-resistant TB (MDR/RR TB) was diagnosed in an estimated 4.1% of new cases and about 19% of previously treated cases. Among these, approximately 6.2% of cases were extensively drug-resistant TB (XDR-TB). An estimated treatment success rate for MDR/RR-TB and XDR-TB was 54% and 30%, respectively. Treatment for MDR/RR-TB and XDR-TB requires a longer therapeutic duration with less effective, more expensive and toxic drugs, leading to a higher rate of treatment failure and mortality. To stop the global spread of MDR/RR-TB and XDR-TB, new anti-TB drugs or combined regimens are urgently needed. Recently, a combined therapeutic strategy consisting of an adjunct immunotherapy and anti-mycobacterial drugs has been proposed and investigated. In our current study, we found that extracellular vesicles isolated from M.tb-infected macrophages synergistically increased M.tb clearance in macrophages in combination with moxifloxacin, a key antibiotic against MDR-TB, in in vitro cell culture infection model and in vivo mouse model. We further demonstrated that extracellular vesicles isolated from M.tb-infected macrophages acted by activating host cytosolic RIG-I/MAVS-dependent pathway and LC3-associated M.tb-containing phagolysosome maturation in host cells. Our results shed light on the development of extracellular vesicle-based host-directed therapy against tuberculosis in humans.