In order to explore the restorative effects of licorice water extract (LWE) on uranium (U)-damaged rats and its underlying mechanisms, gas chromatography-mass spectrometry (GC-MS) metabolomics was employed to explore its metabolic pathways and mechanisms of action. A control group (Ctrl), a model group (MG), a positive drug group (AD), a 1 g/kg LWE group (LD), and a 5 g/ kg LWE group (MD), and 10 g/kg group (HD) (n=8) were established. All groups received a tail vein injection of 3 mg/kg uranium acetate to establish a U-damage model. Following modeling, the LWE groups received oral administration for 7 days. Blood samples were collected from the abdominal aorta 24 h after the final administration to observe changes in body weight, peripheral blood parameters, and organ indices in U-damaged rats treated with LWE. The results show that GC-MS non-targeted metabolomics analysis identified 15 differential metabolites associated with U injury repair. KEGG pathway enrichment analysis indicates that its reparative effects primarily occur through regulating four core pathways: valine-leucine-isoleucine biosynthesis, unsaturated fatty acid metabolism, glyoxylate and dicarboxylic acid metabolism, and glycine-serine-threonine metabolism. These pathways involve amino acid metabolism, lipid homeostasis, and energy metabolism regulation. It is concluded that LWE antagonizes uranium toxicity through multi-target synergistic effects, including mitochondrial function restoration and enhanced antioxidant capacity. This result reveals the multi-target mechanism of LWE in repairing U damage from a metabolic network regulation perspective, providing new insights for traditional Chinese medicine interventions in U-induced injury research.