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Graphical abstract Transforming growth factor β-induced protein (TGFBIp), as an extracellular matrix protein, is expressed TGF-β in some types of cells. Experimental sepsis is mediated by expressed and released TGFBIp in primary human umbilical vein endothelial cells (HUVECs). Cornuside (CNS) is a bisiridoid glucoside compound found in the fruit of Cornus officinalis SIEB. et ZUCC. Based on the known functions of CNS, such as the immunomodulatory and anti-inflammatory activities, we tested whether TGFBIp-mediated septic responses were suppressed by CNS in human endothelial cells and mice and investigated the underlying anti-septic mechanisms of CNS. Data showed that the secretion of TGFBIp by lipopolysaccharide (LPS) and severe septic responses by TGFBIp were effectively inhibited by CNS. And, TGFBIp-mediated sepsis lethality and pulmonary injury were reduced by CNS. Therefore, the suppression of TGFBIp-mediated septic responses by CNS suggested that CNS may be used as a potential therapeutic agent for several vascular inflammatory diseases, with the inhibition of the TGFBIp signaling pathway as the mechanism of action.