Objective To investigate the mechanism of effect of Shutiao Qiji Decoction founded by Zhang Zhen, a national medical master, in the treatment of hyperthyroidism by metabolomics. Methods After adaptive feeding, the rats were divided into 5 blank groups and 18 hyperthyroidism modeling groups. The rats were induced to present hyperthyroidism using levothyroxine, and the modeled hyperthyroid rats were divided into six rats in each of the modeling group, positive drug propylthiouracil (PTU) group and Shutiao Qiji Decoction administration group, and each group was administered with the drug for 6 weeks. The thyroid tissues were stained with hematoxylin-eosin to observe the histopathological changes of the thyroid gland. Serum thyrotropin(TSH), free Triiodothyronine(FT3), free Thyroxine(FT4), anti-Thyroxine receptor antibody (TRAb), interferon γ (IFN-γ), interleukin 6 (IL-6) and tumor necrosis factor (THF-α) levels were measured to observe the index changes. The metabolites in the serum of rats in the blank group, the model group and Shutiao Qiji Decoction administration group were detected by ultra-high pressure liquid chromatography and mass spectrometry, and the differential metabolites were analyzed by correlation pathways. Results Shutiao Qiji Decoction reduced serum TSH levels, increased FT3 and FT4 levels, and significantly reduced the levels of inflammatory factors IFN-γ and TNF-α/IL-6 in hyperthyroid rats(P<0.05). Pathological sections showed that lymphocytes infiltrated in thyroid tissue, enlarged thyroid follicular epithelial cells, enlarged follicular lumen, uneven distribution of intrafollicular cytoplasm and strong glial secretion in the model group, while the lymphocyte infiltration was lighter and the glial distribution was more uniform in the Shutiao Qiji Decoction group than in the model group. The metabolomics technique was used to screen 61 potential serum markers with significant changes, and the analysis of KEGG metabolic pathways revealed that the 2-oxocarboxylic acid metabolic pathway, neuroactive ligand-receptor interaction pathway, glycine serine and threonine metabolic pathways were highly expressed. Conclusion The therapeutic effect of Shutiao Qiji Decoction on hyperthyroidism rats is good, and its mechanism of action is presumed to be related to the 2-oxocarboxylic acid metabolic pathway, neuroactive ligand-receptor interaction pathway, and glycine-serine-threonine metabolism.