Cardiac dysfunction frequently occurs after sepsis and septic shock and contributes to multiple organ failure. Shenfu injection, a well-known Chinese medicine formulation, has recently been demonstrated to possess potential cardio-protective effects, although its effect and mechanism in sepsis-induced myocardial dysfunction remains unclear.To investigate whether Shenfu injection could alleviate myocardial injury and improve cardiac function, a model of sepsis was induced by cecal ligation and puncture (CLP) surgery in C57BL/6 mice. Cardiac function, inflammatory factors, and apoptosis were evaluated in the myocardium.Our results showed that the survival and left ventricular function markedly declined when exposed to CLP compared with the sham procedure. In contrast, Shenfu injection lowered mortality and prevented CLP from triggering left ventricular dysfunction. Moreover, mice treated with Shenfu injection exhibited noticeably decreased myocardial inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocytechemoattractantprotein-1 (MCP-1)] and reduced apoptotic myocardiocytes death compared with mice that had CLP. The activation of myocardial NF-кB detected in septic mice was suppressed by the presence of Shenfu injection, as evidenced by decreased nuclear translocation of the NF-кB p65 subunit. Moreover, Shenfu injection also prevented sepsis-caused decreases in myocardial phospho-Akt and phospho-GSK-3β in septic mice.These data suggest that administration of Shenfu injection attenuates cardiac dysfunction, protects against inflammatory injury, and reduces apoptosis of myocardiocytes during sepsis by activating the AKT/GSK-3β pathway.2022 Annals of Translational Medicine. All rights reserved.