Sepsis is characterized by multiple organ dysfunction, tissue damage and hyper-inflammation. Peganum harmala (PH) is a plant considered for its antibacterial, antioxidant, anticarcinogen and antiinflammatory properties. This study was aimed to evaluate the protective effects of PH extract on tissues and cytokines in sepsis induced by cecal ligation and perforation (CLP) in rats. Forty rats were divided into five groups. Groups were sham-operated (control), CLP, 90 mg/kg PH-treated CLP, 180 mg/kg PH-treated CLP and 180 mg/kg PH-treated control healthy. Animals were sacrificed at the 16th h of the study. Biochemical and histopathological analyses were performed in lung, kidney and blood samples. Both 90 mg/kg and 180 mg/kg doses of PH decreased the level of interleukin-1 beta (IL-1β) and interleukin-10 (IL-10), and high dose of PH reduced the tumor necrosis factor-alpha (TNF-α) in the serum compared to CLP group. The PH also increased the activity of superoxide dismutase (SOD) and the total levels of glutathione (GSH) in the lung and kidney tissues of septic rats. The level of malondialdehyde (MDA) in the lung and kidney tissues was reduced in both PH treated CLP groups. The histopathological results were in accordance with the biochemical results. The CLP + 180 mg/kg PH group had the lowest inflammation score in the lung. In conclusion, the administration of PH has prevented the oxidative stress, the cytokine response and the inflammation in CLP-induced septic rats.