Background: Stroke has always been a big threat around the world, but most severe in China with 2.5 million new stroke cases each year and 7.5 million stroke survivors, which also has laid a heavy burden on social and national healthcare system. The Zhishi Rhubarb Soup (ZRS) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China. In order to explore the potential mechanism of ZRS as the pathogen of stroke. In this study, liquid chromatography mass spectrometry (LC-MS) was employed to uncover the mechanism underlying the effects of ZRS on stroke.Methods: In this study, the quantitative proteomics method LC-MS was used to analyze the proteomic differences of middle cerebral artery occlusion MCAO between normal and after ZSR treatment. Results: Further liquid chromatography mass spectrometry (LC-MS) analysis could observe a total of 3,5006 peptide were identified, 5160.0 proteins identified, of which 4094.0 can be quantified. Differentially expressed proteins with significance were extracted by data analysis and subject to Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Proteins related to brain repair was found to change significantly, including BDNF, IL-10, IL-6, TGF-β，partly demonstrating the effects of ZRS on improving the tissue injury.Conclusion: ZRS was found to contribute to brain repair caused by ZRS treatment, and this could be partly mediated through the anti-inflammation effect by upregulating the vitamin transport. The results confirmed that ZRS presented a unique protein profile that indicated the adaptive mechanisms in acute stroke.