Purslane, as a traditional edible and medicinal herb, has been proven to have good anti-inflammatory activity. In this study, it was clarified that stearic acid was the main anti-inflammatory substance in purslane and could decrease the secretion of inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Meanwhile, the inhibitory effect of liposoluble extract of purslane (PLE) and stearic acid on LPS-induced ulcerative enteritis was determined. LPS-induced enteritis, including body weight loss, reduced weight of the small intestine, and histological intestinal damage, was significantly ameliorated in mice fed PLE and stearic acid. In particular, PLE could significantly reduce the levels of TNF-alpha, IL-6, and interleukin-1beta (IL-1beta) in the small intestine through NF-kappaB and MAPK signaling pathways. Thus, our results proved that purslane could be considered a natural anti-inflammatory medicine to combat LPS-induced inflammation and provide a theoretical basis for future applications in the field of medicine or functional food.