Many patients with sepsis died of heart failure caused by sepsis-induced myocardial depression. Patients with cardiovascular diseases treated by statins have a lower incidence and mortality of sepsis, although the mechanisms remain elusive. To investigate the protective effect of simvastatin on sepsis-induced myocardial depression and to explore possible mechanisms of action. Thirty six adult male Wistar rats were pretreated with simvastatin (0.2μg/g, q12h) for one week before cecal ligation and puncture (CLP). It was found that in simvastatin-treated rats, cardiac function indices, including left ventricular systolic pressure (LVESP) and maximal rate of rise and fall of left ventricular pressure (±dp/dtmax) and mean arterial pressure(MAP) markedly improved. Myocardial cells examined with hematoxylin and eosin (HE) were only partially swollen and degenerated and with fewer inflammatory cells infiltrating. Expressions of TLR4 and NF-κB p65 protein were significantly lower in simvastatin-treated rats than that in sepsis rats at the same time point. Levels of TNF-α, IL-1β, IL-6, MCP-1 and NO in myocardial tissues, together with levels of CTnI in serum were significantly declined in simvastatin-treated rats. Simvastatin has a protective effect on myocardial depression caused by sepsis. The effect may be mediated by the inhibition of TLR4-NF-κB signaling pathway, which leads to reduced levels of downstream inflammatory factors such as TNF-α, IL-1β, IL-6, MCP-1 and NO.