Outer membrane vesicles (OMVs) released by Gram-negative bacteria contribute to infectious diseases. The OMV-associated endotoxin activates cytoplasmic receptors triggering macrophage death, inflammation and sepsis. We have recently shown that OMVs from pathogenic bacteria, such as N. gonorrhoeae, deliver protein toxins to mitochondria to kill macrophages. How OMVs that target mitochondria trigger macrophage death and whether inflammation is induced or not remain unclear. We now have deciphered that OMVs derived from pathogenic bacteria cause mitochondrial dysfunction, which activates intrinsic apoptosis and the NLRP3 inflammasome. Mechanistically, mitochondrial dysfunction reduces host cell protein translation and triggers the loss of the short-lived pro-survival BCL-2 family member, MCL-1, thereby unleashing the mitochondrial death factor, BAK. BAK-induced apoptosis in OMV treated macrophages and potassium ion efflux trigger NLRP3-dependent secretion of the inflammatory cytokine, IL-1ß. Importantly, mice deficient in intrinsic apoptosis contain reduced IL-1 ß serum levels in response to N. gonorrhoeae OMVs. These findings identify OMVs as activators of the host cell mitochondrial apoptosis machinery to trigger both macrophage death and inflammasome activation. Collectively, our findings suggest a host immune surveillance mechanisms that monitors mitochondrial health to detect pathogenic bacteria.