Objective and design: To investigate the potential protective effects of chlorogenic acid (CGA) on acute liver injury caused by lipopolysaccharide (LPS) in mice. Materials and methods: C57BL/6J Mice were pretreated with CGA (50 mg/kg, intraperitoneally) once per day for five days before an overnight LPS challenge (30 mg/kg, intraperitoneally). Severity of liver injury was assessed by histological analysis and determination of serum ALT and AST levels. Expression and activation of key regulators involved in the inflammatory response were respectively determined by real-time RT-PCR and Western Blotting. Results: In contrast to yellow color of the liver in LPS-treated mice, CGA maintained the normal reddish appearance of the liver. Histological analysis indicated that CGA attenuated the infiltration of neutrophil cells and the necrosis of hepatocytes. CGA also decreased the elevated plasma levels of ALT and AST. At the transcriptional level, CGA pretreatment suppressed hepatic mRNA expression of toll-like receptor 4 (TLR4), TNF-α and NF-κB p65 subunit. In contrast, mRNA level of the transcriptional coactivator PGC-1α was restored by CGA. Finally, CGA reduced the phosphorylation of NF-κB p65 subunit in the liver. Conclusion: Our data suggest that CGA has remarkable hepatoprotective effects on LPS-induced liver injury and the possible mechanism is related to its anti-inflammatory action.