BACKGROUND:: Mesenchymal stem cells have immunomodulatory properties. Umbilical cord-derived mesenchymal stem cells have unique advantages, and have a bright future in the clinical treatment of acute lung injury and acute respiratory distress syndrome. OBJECTIVE:: To investigate the protective effect of umbilical cord-derived mesenchymal stem cell transplantation on endotoxin-induced acute lung injury model. METHODS:: Forty-eight healthy male Sprague Dawley rats were randomly divided into normal control group, acute lung injury group and umbilical cord-derived mesenchymal stem cell transplantation group. The rats in the acute lung injury group and umbilical cord-derived mesenchymal stem cell transplantation group were used to establish the acute lung injury model through intratracheal instillation of endotoxin. One hour after modeling, rats in the umbilical cord-derived mesenchymal stem cell transplantation group were instilled with umbilical cord-derived mesenchymal stem cells suspension intratracheally, and the rats in the normal control group and acute lung injury group were instilled with normal saline in the same dose intratracheally. After treated for 24 and 72 hours, the pathological changes of the lung tissue were observed, and the histological score, wet and dry weight ratio of the lung tissue, myeloperoxidase activity and the levels of interleukin-6, interleukin-10 and tumor necrosis factor-α were detected. RESULTS AND CONCLUSION:: Umbilical cord-derived mesenchymal stem cell transplantation could attenuate lung injuries in rat models of acute lung injury. Compared with acute lung injury group, the histological score, wet and dry weight ratio of the lung tissue, myeloperoxidase activity and the levels of interleukin-6 and tumor necrosis factor-α in the umbilical cord-derived mesenchymal stem cell transplantation group were decreased at different time points, while the level of interleukin-10 was increased. Umbilical cord-derived mesenchymal stem cells have protective effect on endotoxin-induced acute lung injury models; the protection mechanisms may be that the umbilical cord-derived mesenchymal stem cell transplantation can maintain the balance between inflammatory mediators and anti-inflammatory mediators in lung tissues.