Abstract: Glycyrrhetinic acid (GA) is the bioactive ingredient in Glycyrrhizae Radix et Rhizoma. Our previous study has reported that GA has protective effect on realgar-induced hepatotoxicity. However, the details of the hepatoprotective mechanisms of GA on realgar-induced liver injury remain to be elucidated. In the study, mice were divided into control, GA-control, realgar, and co-treated groups. Their liver tissues were used for metabonomics study by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method. The results illustrate that GA significantly ameliorate the liver injury and metabolic perturbations caused by realgar. Some metabolites, such as phenylalanine, pyroglutamic acid (PGA), proline, carnitine, nicotinamide, choline, lysophosphatidylcholine (LPC) 16 : 0 and LPC 18 : 2 were found responsible for the hepatoprotective effect of GA. These metabolites are associated with the methylation metabolism of arsenic, cell membrane structure, energy metabolism and oxidative stress. From the results of this study, we infer that the potential hepatoprotective mechanism of GA on realgar-induced liver injury may be associated with reducing arsenic accumulation and its methylation metabolism in the liver, promoting the conjugation of arsenic and GSH to play detoxification effect, and ameliorating the liver metabolic perturbations caused by realgar.