Background: Lepidium sativum (LS) is a very potent and often used as anti-cancer is largely limited due to the dose-related toxic effects. The present study investigated the protective role of LS that can reduce the liver injury induced by LPS.Methods: Forty white male mice were randomly divided into five groups: the vehicle control group, LPS group, LPS plus LS group, LS pretreated plus LPS group and LS + LPS + LS group. Mice were sacrificed at 2, 4, 8, 16, 24 and 48h. Blood and liver samples were collected for the experimental investigations. Biochemical analysis, histopathological studies and molecular investigation carried out for different groups used. Result: Biochemical analysis for serum AST, ALT, LDL and HDL levels were determined to evaluate liver status. Oxidative stress of liver examined through determination of oxidative enzymes. Furthermore, proinflammatory (IL-6 and TNF-α) and anti-inflammatory (IL-4 and IL-10) cytokines were investigated. Histopathological liver sections were examined to show the alterations due to LPS injection. Biochemical analysis showed a significant modulatory effect of LS on the LPS challenged mice. Histopathological studies showed that LPS caused liver alterations, such as necrosis, infiltrations of neutrophils, sinusoid congestion and hepatocellular degeneration in the liver. These histopathological modulations were significant by LS pretreatment. These findings indicate that LS has a significant hepatoprotective effect on LPS-induced liver injury in mice model.