Physalin is the main component of Physalis alkekengi L.var.franchetii. Based on research on Chinese herbal medicine, it is mainly used to treat respiratory diseases. LPS-induced acute lung injury (ALI), characterized by pulmonary edema and respiratory distress, was treated with Physalin. Firstly, Rats were treated with LPS followed by the gavages of Physalin. In vitro, Physalin was applied to RLE-6TN cell line pre-treated with LPS. LPS caused inflammation, hemorrhages, and lung dysfunction and apoptosis in rats. Physalin significantly attenuated these adverse effects, decreased the expression of IL-1β and TNF-α in lung tissues. Increased the expression of inhibitor of NF-κB (IκB), decreased the translocation of NF-κB and its downstream protein (COX-2 and IL-1β), and MAPK phosphorylation. In vitro, Physalin increased alveolar epithelial cells viability, inhibited activation of MAPK and release of inflammatory factors. Physalin can achieve the effect of treating inflammation caused by LPS in rats through reducing the phosphorylation level of IκB, NF-κB, ERK1/2, JNK and p38 MAPK, thereby reducing the expression of inflammatory factors TNF-α, COX2 and IL-β, and reducing the apoptosis of alveolar epithelial cells both in vivo and in vitro.