Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration. [Display omitted] • GSDME is expressed by neurons and activated by mitochondrial toxins • Neuronal GSDME drives local mitochondrial damage and axon loss prior to cell death • ALS/FTD proteins activate GSDME and drive neurite loss in mouse and human neurons • SOD1G93A GSDME KO mice have rescued disease progression and motor neuron loss Gasdermin-E is a pore-forming molecule that is expressed in neurons. When activated, this molecule rapidly targets and destroys mitochondria. In neurons, toxin exposure activates GSDME and drives mitochondrial and axonal destruction. The genetic inhibition of GSDME rescues axon loss in amyotrophic lateral sclerosis (ALS) patient-derived motor neurons and ameliorates disease in a mouse model of ALS. [ABSTRACT FROM AUTHOR]