Legionella invade macrophages within the human lung to cause a severe pneumonia, known as Legionnaires’ Disease. The intracellular life-cycle renders Legionella resistant to many common antibiotic treatments, resulting in high fatality rates in critically ill patients. Here, we show that targeting the host cell anti-apoptotic protein, BCL-XL, restricts Legionella infection, both in vitro and in vivo, by inducing apoptosis of infected macrophages. Using a novel live-cell imaging technique to follow Legionella infection of primary bone marrow-derived macrophages (BMDMs) in real-time, we show that Legionella-infected macrophages depend critically upon the anti-apoptotic activity of BCL-XL, but not other Bcl-2 family members, for viability. In the absence of BCL-XL, Legionella-infected cells undergo apoptosis, which abolishes bacterial replication and dissemination. Legionella infection can be fully restored by inhibiting mitochondrial apoptosis, either via BAX/BAK deletion or caspase inhibition. Remarkably, a single dose of BCL-XL-targeted BH3-mimetic therapy significantly reduces Legionella burden in the lungs and prevents lethal bacterial infection in mice. Mechanistically, we show that Legionella inhibits host protein translation, which sensitises macrophages to BCL-XL expression. Together, these results demonstrate that Legionella-infected macrophages are specifically and profoundly sensitive to apoptotic cell death following the loss, or inhibition, of BCL-XL. Thus, the re-purposing of anti-cancer treatments, like BH3 mimetic therapy, represents a promising strategy for the treatment of intracellular pathogens that show increased antibiotic resistance.