Drug-induced liver injury (DILI) is an adverse drug reaction that results in acute liver failure or even death in severe cases. Recently, the incidence of DILI caused by Psoraleae Fructus (PF), a widely used tonic in clinical medicine, has increased. However, no effective method for mitigating hepatotoxicity has been identified. Glycyrrhizae Radix et Rhizoma (GR) is a functional food with known detoxifying and hepatoprotective properties. Therefore, this study aimed to investigate the potential effect of GR in mitigating PF-induced hepatotoxicity and to elucidate the underlying mechanisms. A rat model of lipopolysaccharide (LPS)-induced immune stress was established to examine the ameliorative effect of GR on PF-induced hepatotoxicity. GR reduced PF-induced increase in the levels of liver injury markers, downregulated the levels of inflammatory factors and oxidative stress, and ameliorated pathological changes in liver tissue. Pathway analysis of 37 differentially expressed metabolites following GR treatment showed that the metabolites were mainly enriched in pathways associated with the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. In vitro, GR effectively inhibited PF-induced NLRP3 inflammasome activation in LPS-stimulated bone marrow-derived macrophages (BMDMs), providing a novel therapeutic strategy for managing PF-induced hepatotoxicity and guidance for the rational clinical use of PF.