Liquiritigenin (LQ) has protective effects against various hepatotoxicities. However, its specific role on arsenic trioxide (ATO)-induced hepatotoxicity and the related biomolecular mechanisms remain unclear. The purpose of this study is to explore the protective actions of LQ on ATO-induced hepatotoxicity and its biomolecular mechanisms in mice. LQ was administered orally at 20 and 40 mg/kg per day for seven consecutive days with an intraperitoneal injection of ATO (5 mg/kg). Liver injury was induced by ATO and was alleviated by treatment with LQ as reflected by reduced histopathological damage of liver and decreased serum ALT, AST, and ALP levels. The generation of intracellular ROS induced by ATO was attenuated after LQ treatment. The levels of SOD, CAT, and GSH were elevated with LQ administration while MDA levels decreased. LQ mitigated elevated TNF-α and IL-6 levels as well as the hepatic mitochondrial damage caused by ATO. Moreover, LQ upregulated the expression of LC3-II and enhanced autophagy in the liver of ATO-induced mice. Further studies indicated that LQ significantly suppressed the expression of p-PI3K, p-AKT, and p-mTOR in ATO-induced mice. In conclusion, our findings show that LQ protects against ATO-induced hepatotoxicity due to its antioxidant and anti-inflammatory activities and enhancement of autophagy mediated by the PI3K/AKT/mTOR signaling pathway in mice.