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Background: Jujuboside A (JuA), as a main effective component of Jujubogenin, which was extracted from the seed of Ziziphus jujuba Mill, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS) in mouse models. Method: Wide type C57BL/6J mice were randomly divided into four groups: ddH2O+control, ddH2O+JuA, LPS+NS and LPS +JuA, and the cardiac function of septic mice were detected by echocardiography. Moreover, the survival rate at each time point was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, Western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detecting the number of autophagosomes. Finally, the expression of autophagy-related and oxidative stress-related proteins was analyzed by western blotting and immunohistochemistry staining. Results: Results showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and enhanced autophagy. Moreover, JuA pretreatment also significantly decreased oxidative stress and nitrodative stress, as evidenced by downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3‑MA significantly abolished the effect of JuA on autophagic activity in SIC. Conclusion: In conclusion, the findings indicated that JuA enhanced autophagy blocking inflammasome-mediated cardiomyocyte apoptosis and suppress myocardial iNOS and gp91 expression to improve cardiac function of SIC in septic mice.