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Objective To study the mechanism of the intervention of total flavonoids from Zhongjiefeng (sarcandra[twig and leaf]) on immune thrombocytopenia (ITP) using metabolomics techniques. Methods Using Excel random function, 48 male SD rats were randomly divided into the normal control group, the model group, the total flavonoids from Zhongjiefeng low-, medium-, and high-dose groups, and the prednisolone acetate group, with 8 rats in each group. Except for the normal control group, rats in other groups were injected intraperitoneally with rabbit anti-rat platelet serum (5 mL/kg) on days 1, 3, 4, 6, 7, and 8 to replicate an ITP rat model. Rats in the normal control group were injected intraperitoneally with an equal volume of physiological saline. Drug intervention was given on the modeling day once a day. The total flavonoids from Zhongjiefeng low-, medium-, and high-dose groups were gavaged with 31.5, 63.0, and 94.5 mg/kg of total flavonoids from Zhongjiefeng, respectively. The prednisolone acetate group was injected intraperitoneally with 10.0 mg/kg of prednisolone acetate. On days 0, 3, 6, and 9, the number of peripheral platelets in each group of rats was dynamically detected. On day 10, the spleen mass was measured and the spleen index was calculated. Screening and identification of differential metabolites in the spleen of rats in each group were carried out using ultra-high-performance liquid chromatography coupled with four-stage rod time-of-flight mass spectrometry technology and multivariate statistical analysis, and pathway enrichment analysis was conducted. Results Compared with the normal control group, the model group showed a decrease in peripheral blood platelets on days 6 and 9, an increase in spleen mass, and an increase in spleen index(P<0.05). Compared with the model group, the number of peripheral platelets on day 6 and 9 of the total flavonoids from Zhongjiefeng low-, medium-, and high-dose groups were increased, the spleen mass of the total flavonoids from Zhongjiefeng high-dose group was decreased, and the spleen indexes of the total flavonoids from Zhongjiefeng medium- and high-dose groups were decreased (P<0.05). Through metabolomics analysis of the spleen, 24 biomarkers related to ITP were identified. Of these, 21 were reduced in the total flavonoids from Zhongjiefeng high-dose group, which were mainly involved in linoleic acid metabolism, cysteine and methionine metabolism, and glycerol phospholipid metabolism. Conclusion The total flavonoids from Zhongjiefeng may restore the normal regulatory ability of the immune system by regulating spleen linoleic acid metabolism, cysteine and methionine metabolism, and glycerol phospholipid metabolism, in order to inhibit excessive platelet destruction and exert a therapeutic effect on ITP. [ABSTRACT FROM AUTHOR]