Plasma extracellular vesicles (EVs) are cell-derived lipid particles and reportedly play a role in sepsis pathogenesis. This study aimed to identify EV cargo proteins in septic patients and explore their association with key sepsis pathophysiology. Plasma EVs were subjected to Tandem Mass Tag (TMT)-based quantitative proteomic analysis. We identified 522 differentially expressed (DE) EV proteins in septic patients (n = 15) compared to the healthy controls (n = 10). The KEGG analysis of the DE proteins revealed multiple functional pathways linked to sepsis, e.g., complement/coagulation, platelet activation, phagosome, inflammation, and neutrophil extracellular trap formation. Weighted Gene Coexpression Network Analysis of 1,642 EV proteins identified nine unique protein modules, some of which were highly correlated with the sepsis diagnosis and diverse endotype markers including organ injury, inflammation, coagulopathy, and endothelial activation, and mortality. ROC analysis revealed a list of novel EV proteins that exhibited strong diagnostic performance. Cell type-specific enrichment analysis revealed the cellular origins of EVs, including immune and epithelial cells, neurons, and glial cells. Thus, the current study discovered complex proteomic signatures in plasma EVs that are closely associated with key pathophysiological responses in sepsis. These findings support the importance of EV cargo proteins in the patients' immune responses, coagulation, and endothelial activation and lay the foundation for future mechanistic study of plasma EVs and their clinical application as potential diagnostic and prognostic markers.