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The therapeutic potential of the antimicrobial peptide cathelicidin (Camp) administration in sepsis has been widely investigated. However, little is known about the pathophysiological roles of cathelicidin in septic cardiomyopathy. In a lipopolysaccharide (LPS)‐induced endotoxaemic model, we found that the mRNA and protein expression of cardiac cathelicidin were induced in C57BL/6J wild‐type (WT) mice upon LPS challenge, accompanied by increased circulating cathelicidin levels. We showed that this peptide was mainly derived from neutrophils and monocytes/macrophages. Camp deficiency exacerbated LPS‐induced myocardial depression, while the administration of CRAMP (the mature form of mouse cathelicidin) decreased the LPS‐induced mortality in a D‐galactosamine hydrochloride (D‐GalN)‐sensitized endotoxin shock model. In vivo, LPS‐treated Camp knockout mice had a significant higher protein level of myocardial and circulating tumour necrosis factor‐alpha (TNF‐α), a major contributing factor to septic cardiomyopathy, compared to LPS‐treated WT mice, while CRAMP administration inhibited LPS‐induced TNF‐α production in the heart and plasma in D‐GalN‐sensitized endotoxaemic mice. In vitro, CRAMP treatment suppressed LPS‐induced Tnf‐α mRNA expression in cultured neonatal mouse cardiomyocytes and reduced TNF‐α secretion in the culture supernatant. The inhibitory effects of CRAMP on TNF‐α production may be related to its neutralizing ability of LPS, since CRAMP application had no effects on another toll‐like receptor 4 ligand paclitaxel‐induced Tnf‐α mRNA expression in cardiomyocytes. These findings suggest that LPS‐induced cathelicidin protects the heart against myocardial depression partly through the inhibition of TNF‐α production via neutralizing LPS.