<p>Septic cardiomyopathy (SCM) is heart failure caused by sepsis and often causes an excessive inflammatory response. As a natural sesquiterpene alcohol, the anti-inflammatory properties of β-Eudesmol have been confirmed in various inflammatory diseases, but its effect on SCM remains unclear. Therefore, this study aimed to investigate the effect of β-Eudesmol on SCM and elucidate its potential mechanisms. An SCM rat model was established by cecal ligation and puncture (CLP) for experimental investigation. The levels of cytokines as well as the indicators of cardiac function injury, BNP and cTnl, were detected by ELSA. Myocardial tissue injury was detected by HE staining and TUNEL staining. The expression of key genes and proteins was detected by RT-qPCR and western blotting. The results show that treatment with β-Eudesmol alleviated myocardial apoptosis and inflammatory injury in SCM rats. Specifically, it significantly reduced serum levels of BNP and cTnI, and decreased the levels of IL-6, IL-1β, TNF-α, and LPS, while also inhibiting inflammatory cell infiltration and apoptosis within the myocardial tissue. Furthermore, we found that β-Eudesmol treatment also reduced serum IL-17 levels in rats and inhibited the expression of IL-17A, CXCL1, CXCL2, and CCL20 mRNA and p-GSK3B/GSK3B. Mechanistic studies revealed that β-Eudesmol enhanced GSK3B activity by inhibiting GSK3B phosphorylation, thereby suppressing the expression of IL-17 and its mediated chemokines, and ultimately alleviating inflammatory injury to the SCM. Overall, β-Eudesmol alleviates SCM myocarditis inflammation by inhibiting IL-17-mediated chemokine expression through enhancing GSK3B activity.</p> Graphical Abstract <p></p>