Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity. Display omitted •Infection-associated ER stress initiates mitochondrial damage through IRE1α•Mitochondrial damage is required for IRE1α-dependent IL-1β production•IRE1α promotes mitochondrial damage via NLRP3, caspase-2, and Bid•The NLRP3-caspase-2 axis drives general ER stress-induced inflammasome activation The endoplasmic reticulum stress response modulates inflammatory responses during chemical stress or microbial infection. O’Riordan and colleagues report that endoplasmic reticulum stress sensor IRE1α induces ROS-dependent NLRP3 translocation to mitochondria. NLRP3 stimulates the caspase-2-Bid mitochondrial damage pathway, leading to release of mitochondrial danger signals that activate the inflammasome.