Dysregulated inflammation is closely associated with increased mortality in sepsis. Platelets have emerged as key inflammatory cells implicated in the pathology of sepsis, including the development of thrombosis, thrombocytopenia, and neutrophil extracellular traps (NETs). Platelet’s contributions to rapid clinical deterioration and dysregulated inflammation in sepsis have not been defined. In our cohort, the incidence of thrombocytopenia, thrombocytopathy and excessive inflammatory cytokines released in patients with severe sepsis were significantly increased. Platelet proteomic analysis revealed significant up-regulation of Gasdermin D (GSDMD). Using platelet-specific Gsdmd deficient mice, we demonstrated a requirement for GSDMD in triggering platelet pyroptosis in cecal ligation and puncture (CLP)-induced sepsis. We further demonstrated that GSDMD-dependent platelet pyroptosis was induced by high levels of S100A8/A9 targeting platelet toll-like receptor 4 (TLR4). Pyroptotic platelet-derived oxidized mitochondrial DNA (ox-mtDNA) potentially promoted NET formation, which in turn contributed to platelet pyroptosis via the release of S100A8/A9, forming a positive feedback loop that led to excessive inflammatory cytokines release. Both pharmacological inhibition using Paquinimod and genetic ablation of the S100A8/A9-TLR4 signaling axis suppressed GSDMD-dependent platelet pyroptosis, thereby alleviating NET-mediated inflammation and improving survival in CLP-induced sepsis mice. Taken together, these findings provide new insights into the proinflammatory role of platelet pyroptosis in severe sepsis.