Sepsis-induced myocardial dysfunction represents a major cause of death. Alamandine is an important biologically active peptide. The present study evaluated whether alamandine improves cardiac dysfunction, inflammation, and apoptosis, and affects the signaling pathways involved in these events. Experiments were carried out in mice treated with lipopolysaccharide (LPS) or alamandine, and in neonatal rat cardiomyocytes. Alamandine increased the ejection fraction and fractional shortening, both of which were decreased upon LPS infusion in mice. LPS and alamandine reduced blood pressure, and increased the expression of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in the heart in mice. The LPS-induced decrease in α-myosin heavy chain (MHC) and β-MHC, and increase in S100 calcium binding protein A8 (S100A8) and S100A9, were reversed by alamandine pre-treatment. Alamandine pre-treatment prevented LPS-induced myocardial inflammation, apoptosis and autophagy. LPS increased p-ERK, p-JNK, and p-p38 levels, which were inhibited by alamandine. Dibutyryl cyclic AMP (db-cAMP) increased p-ERK, p-JNK, and p-p38 levels, and reversed the inhibitory effects of alamandine on the LPS-induced increase in p-ERK, p-JNK, and p-p38. Moreover, db-cAMP reduced the expression of α-MHC and β-MHC in cardiomyocytes, and reversed the almandine-induced attenuation of the LPS-induced decrease in α-MHC and β-MHC. These results indicate that alamandine attenuates LPS-induced cardiac dysfunction, resulting in increased cardiac contractility, and reduced inflammation, autophagy, and apoptosis. Furthermore, alamandine attenuates sepsis induced by LPS via inhibiting the mitogen-activated protein kinases (MAPKs) signaling pathways.