Abstract: The aim of the present study was to investigate the effects and mechanisms of lidocaine on lipopolysaccharide(LPS)-induced matrix metalloproteinase(MMP)-9 and MMP-2 activity in plasma, and the effects of lidocaine on LPS-induced acute lung injury(ALI). Mice were pretreated with lidocaine(2, 4, 8 mg/kg )for 30 minutes, and then treated with 10 mg/kg LPS(ip)for 12 h to induce ALI. The 7-day survival rate and lung wet/dry weight ratio of mice were monitored. Phosphorylation level of p38 was measured by western blot. The activity of MMP-9 and MMP-2 in plasma was evaluated by gelatin zymography. The results showed that pretreatment with lidocaine could significantly reduce the death rate of ALI mice as well as the lung wet/dry weight ratio in a dose-dependent manner and suppress the activity of MMP-9 and MMP-2 in plasma. Moreover, lidocaine also markedly inhibited LPS-induced upregulation of p-p38 in a dose-dependent manner. In conclusion, lidocaine alleviated LPS-induced acute lung injury by suppressing MMP-9 and MMP-2 activity.