Elephantopus scaber (ES, Teng-Khia-U) has been traditionally used for the treatment of nephritis, pain, and fever; however, the direct evidence is lacking. We investigated the effect of ES on lipopolysaccharide (LPS) induced inﬂammation of BV-2 microglial cells and acute liver injury in Sprague-Dawley (SD) rats. Our results showed that ES reduced LPS-induced nitric oxide (NO), interleukin (IL)-1, IL-6, reactive oxygen species (ROS), and prostaglandin (PGE2) production in BV-2 cells. ES signiﬁcantly decreased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in LPS-treated rats. Furthermore, the water extract, but not the ethanol extract, of ES dose-dependently inhibited LPS-induced JNK, p38 mitogen-activated protein kinases (MAPK), and slightly inhibited cyclooxygenase (COX-2) in BV-2 cells but decreased p38 MAPK and COX-2 expressions in the liver of LPS-treated rats. Taken together, these results indicate that the protective mechanism of ES involves an antioxidant effect and inhibition of p38 MAP kinase and COX-2 expressions in LPS-stressed acute hepatic injury in SD rats.