Sepsis is a serious medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. Amiodarone is a class III antiarrhythmic agent, a multichannel blocker (Ca++, Na+, and K+), and a noncompetitive alpha- and beta-adrenergic blocker in cardiac cells. The present study aimed to determine whether amiodarone was protective against experimentally induced cecal ligation and puncture sepsis in rat lung tissue. The relationship between its probable protective effect and antioxidant/anticytokine action biochemically and histopathologically was also examined. Five groups of rats were used, each composed of 20 rats: (1) the sham-operated control group; (2) the CLP group; (3) the 25-mg/kg amiodarone-treated control healthy group; (4) the 50-mg/kg amiodarone-treated CLP group; and (5) the 50-mg/kg amiodarone-treated CLP group. A CLP polymicrobial sepsis model was applied to the rats. All groups were sacrificed 16 h later, and lung and blood samples were analyzed histopathologically and biochemically. Twenty-five and 50 mg/kg amiodarone decreased the level of interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha in serum and 8-iso-prostaglandin F2 alpha level in lung tissue. They increased the activities of superoxide dismutase and levels of total glutathione in lung tissues of rats. Histopathological scores and examinations were in accordance with the biochemical results. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups. The CLP + amiodarone 50 mg/kg group had the lowest inflammation score among CLP groups. Our results indicate that administration of amiodarone prevented oxidative stress and cytokine action and protected lung tissue during sepsis cascade.