Activated macrophages undergo a metabolic switch to aerobic glycolysis accumulating Krebs cycle intermediates that alter transcription of immune response genes. Here we extend these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. This succination of GSDMD prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. Administration of fumarate protects in mice against LPS shock, alleviates familial Mediterranean fever and experimental autoimmune encephalitis (EAE) by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a novel mechanism of action for fumarate-based therapeutics including dimethyl fumarate used to treat multiple sclerosis.