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Graphical abstract Figure. No Caption available. HighlightsCopper‐laden rat model was established to study the therapeutic effect of Gandou decoction (GDD) on hepatolenticular degeneration (HLD).A UPLC‐Q‐TOF/MS‐based serum metabolomic approach was used to further provide a global view of GDD treatment.GDD could provide satisfactory therapeutic effects on HLD.GDD could restore the impaired lipid metabolism, amino metabolism and glucose metabolism in Copper‐laden rats. Abstract The direct cause of hepatolenticular degeneration (HLD) is copper metabolic disorder caused by autosomal recessive inheritance. Gandou decoction (GDD), a classical traditional Chinese medicine formula, exhibits unambiguous therapeutic effect on HLD in China for decades. However, the mechanism of effect on HLD is not clear. With this purpose, the effects of copper content and histopathology inspection on the HLD rat model were investigated. Then, metabolomics study based on ultra‐performance liquid chromatography quadrupole‐time‐of‐flight mass spectrometry (UPLC‐Q‐TOF/MSE) analysis and multivariate statistical analysis was adopted to further reveal the mechanism of action of GDD against HLD. The results showed that the characteristics of liver tissues after GDD treatment were significantly reversed, close to the control group, suggesting that GDD has a therapeutic effect on HLD. Furthermore, HLD interferes with 2 metabolites of the metabolic pathway in rats. Among them, up‐regulation of Lactic acid, Tryptophan, Phenylalanine, Triacylglycerol and down‐regulation of Linoleic acid, Alpha Linolenic acid, Phosphatidylcholine, Taurine is particularly significant. Analysis of metabolic pathways by a unique pathway analysis revealed significant changes in several pathways including lipid metabolism, amino metabolism and glucose metabolism in HLD. This study showed that GDD could provide satisfactory therapeutic effects on HLD and metabolomics study can be utilized to further understand the molecular mechanisms.