Although isoniazid preventive therapy (IPT) for tuberculosis (TB) is recommended by the WHO for people living with HIV, its use remains limited. Bedaquiline long-acting (BDQ-LAI), an injectable antitubercular drug with a long terminal half-life (23 weeks), may simplify TB prevention, akin to long-acting antivirals. This study evaluated BDQ-LAI as a preventive therapy using a novel murine model.Methods: Seventy-two female Balb/c mice (6 weeks old) were assigned to three treatment groups receiving BDQ-LAI intramuscularly at low, middle or high dosing (N=24/group), and one untreated control group (N=30). Ten days post-treatment, all mice were infected intranasally with 32 CFU/mouse of M. tuberculosis H37Rv. On day 1 post-infection, six untreated mice were sacrificed to assess baseline lung CFU and plasma exposure. Lung CFU counts and drug levels in plasma and lungs were assessed on days 14, 21, 28, and 100 in six mice per group.Results: in the untreated control group, CFU increased up to 5.7+/-0.6 log10 CFU at D100.The low dose of BDQ-LAI, did not prevent bacillary growth (5.4+/-0.7 log10 CFU at D100) and had a minimal impact on bacterial replication. The high BDQ-LAI dose completely prevented bacillary growth at all time-points evaluated. The middle BDQ-LAI dose displayed intermediate activity with 2/6 mice culture positive at D14, D21 and D28 (with 0.6 to 1.2 average log10 CFU count) and no positive mouse at D100.Conclusions: BDQ-LAI demonstrated dose-dependent protection against TB in mice, with complete prevention at the highest dose. These findings support further investigation of BDQ-LAI as a simplified, long-acting TB preventive therapy, particularly beneficial for high-burden regions and global TB control efforts.