Objective: To investigate the effect of hydrogen inhalation on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the underlying molecular mechanisms. Methods: Thirty-two male SD rats were randomly divided into 4 groups (n=8), namely the normal saline group (SA), saline with 2% hydrogen gas inhalation group (SH group), ALI group, and ALI with hydrogen inhalation group (LH group). In the two ALI groups, ALI was induced by intraperitoneal injection of 15 mg/kg LPS. Treatments with inhalation of 2% hydrogen gas for 6 h was administered after the injection of LPS or saline. The concentrations of tumor necrosis factor-α (TNF-α) in the lung tissue and serum were examined with ELISA. The expression of p38 MAPK in the lung tissue was detected by Western blotting. Results: Hydrogen inhalation decreased the expression of p-p38 MAPK in the lung tissue, and significantly reduced TNF-α content in the lung tissue and serum of rats with ALI. Conclusion: Hydrogen inhalation can decrease the expression of TNF-α in the lung tissue and serum, and this effect may be related with reduced p38 MAPK expression and inhibition of p38 MAPK activation.