Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of pathogen infection. UPR signalling is essential for the secretory functions of immune cells but whether it plays a direct role in the innate-immune sensing of pathogens is unknown. Using metabolomics and complementary methods, we observed that pharmacological ER stress reprogrammed cellular metabolism and enhanced host immune and microbicidal functions to inhibit bacterial infection. This microbicidal host response required the STAT1 transcription factor which mediates interferon responses to infection and was activated by ER-protein misfolding in a UPR-dependent manner. Phosphoproteomics then showed that UPR-kinase activity initiates JAK/STAT1-signalling, alongside adjacent pro-inflammatory pathways, to drive STAT1-mediated immune responses to ER stress. Finally, we demonstrated that blockade of the UPR by secreted effectors from the bacterial pathogen Legionella pneumophila inhibited STAT1 signalling during infection. Our findings reveal a direct link between the UPR and STAT1-mediated immunity as well as a common virulence mechanism used by bacterial pathogens to inhibit this pathway and evade host immune responses to ER stress.