Depression is the most prevalent psychiatric disease, and its pathogenesis is still unclear. Currently, studies on the pathogenesis of depression are mainly focused on the brain. The liver can modulate brain function via the liver-brain axis, indicating that the liver plays an important role in the development of depression. This study aims to explore the protective effect of quercetin against chronic unpredictable mild stress (CUMS)-induced metabolic changes and the corresponding mechanisms in the rat liver based on untargeted metabolomics technology. In this study, 96 male rats were divided into six groups: control, different doses of quercetin (10 mg per kg bw or 50 mg per kg bw), CUMS, and CUMS + different doses of quercetin. After 8 weeks of CUMS modeling, the liver samples were collected for metabolomics analysis. A total of 17 altered metabolites were identified, including D-glutamic acid, S-adenosylmethionine, lithocholylglycine, L-homocystine, prostaglandin PGE2, leukotriene E4, cholic acid, 5-methyltetrahydrofolic acid, taurochenodeoxycholic acid, S-adenosylhomocysteine, deoxycholic acid, folic acid, L-methionine, leukotriene C5, estriol-17-glucuronide, PE, and PC, indicating that methionine metabolism, bile acid metabolism, and phosphatidylcholine biosynthesis are the major pathways involved in CUMS-induced hepatic metabolic disorders. Hepatic methylation damage may play a role in the pathophysiology of depression, as evidenced by the first discovery of the abnormality of hepatic methionine metabolism. Abnormal changes in hepatic bile acids may provide stronger evidence for depression pathogenesis involving the microbiota-gut-brain axis, suggesting that the liver is involved in depression development and may be a treatment target. The quercetin treatment alleviated the CUMS-induced liver metabolism disorder, suggesting that quercetin may protect against depression by regulating liver metabolism.