Sodium butyrate (SB) is a short chain 4-carbon fatty acid salt naturally exists in animal fats. Previous studies have proven that sodium butyrate has many beneficial functions such as anti-tumor and anti-inflammatory actions. In the current study we investigated the effect and possible mechanism of sodium butyrate in LPS-induced acute lung injury (ALI). ALI was induced by intratracheal administration of LPS (10?mg/kg) in male BALB/c mice. Sodium butyrate (500?mg/kg) was administered intraperitoneally 30?min prior to LPS exposure. We found that sodium butyrate significantly protected animals from LPS-induced ALI as evidenced by decreased the lung wet to dry weight ratio, total cells, neutrophils, macrophages, myeloperoxidase (MPO) activity, and lung histological damage compared to vehicle control. Sodium butyrate pretreatment markedly inhibited the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Furthermore, sodium butyrate pretreatment dramatically suppressed HMGB1 release and NF-κ B activation. Together, these results suggest that sodium butyrate pretreatment protects mice from LPS-induced acute lung injury, possibly through the modulation of HMGB1 and inflammatory responses.