We aimed to investigate the role of prior treatment of simvastatin on cytokine response, energy levels, and apoptotic molecules on muscle tissue in rats treated with lipopolysaccharide (LPS) during the early phase of sepsis. Male Wistar albino rats (200-250 g) were divided into four groups: control, endotoxemia (20 mg/kg, i.p.), simvastatin (20 mg/kg, p.o.), and simvastatin + endotoxemia. Four hours after the beginning of the experiments, 8 rats from each group were sacrificied and gastrocnemius muscle tissue was dissected to examine for histologic changes using hematoxylin-eosin staining. The gene expressions of TNF-alpha, IL-10 and Bcl-2, Bax, and Caspase-3 mRNA levels were analyzed using real-time polymerase chain reaction. Creatine, creatine phosphate, adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) levels were investigated in muscle tissue using high performance liquid chromatography. ATP values were found low in the endotoxemia group and increased in the Simvastatin + endotoxemia group compared with the endotoxemia group (P < 0.05). Caspase-3, Bax, and TNF-alpha levels were significantly higher in the endotoxemia group than in the other groups (P < 0.01). In the simvastatin + endotoxemia group, Bcl-2 and TNF-alpha (P < 0.05), and IL-10 (P < 0.01) levels were higher than other groups. Muscle sections of the LPS group showed inflammation and atrophic areas. Tissue injury was reduced in the simvastatin + endotoxemia groups sections. Sepsis caused an increase of pro-inflammatory cytokine TNF-alpha and pro-apoptotic proteins; caspase-3 and Bax in muscle tissue may also have caused tissue damage. Pretreatment of simvastatin reduced muscle tissue damage by increasing levels of the anti-inflammatory cytokine IL-10 and the anti-apoptotic protein Bcl-2.