AbstractNeurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV‐induced neuronal cell death remain enigmatic. Here, we report that lytic HSV‐2 infection of human neuron‐like SH‐SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV‐2‐induced GSDME‐mediated cell death occurs downstream of replication‐induced endoplasmic reticulum stress driven by inositol‐requiring kinase 1α (IRE1α), leading to activation of caspase‐2, cleavage of the pro‐apoptotic protein BH3‐interacting domain death agonist (BID), and mitochondria‐dependent activation of caspase‐3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC‐derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress‐driven pathway to execute GSDME‐mediated cell death and promote inflammation.