Ischemic stroke (IR), a leading cause of death worldwide, is one of the most common disorders of the central nervous system and has a poor prognosis. Our previous clinical study had found that Qilong Quyu (QLQY) formula, a currently used hospital preparation derived from classical prescription of TCM, could improve the neurological deficits of the patients suffering stroke. However, the neuroprotective mechanism of QLQY formula remains unclear. In this study, firstly we confirmed that QLQY formula treatment could significantly alleviate ischemia reperfusion (IR)-induced infarct volume and neuronal death in a dose-dependent manner in middle cerebral artery occlusion (MCAO) model mice. Then, proteomics analysis was performed between MCAO model mice treated orally with or without QLQY formula. In total, 85 differentially expressed proteins (DEPs) were observed in mice after QLQY formula treatment, of which 24 DEPs were upregulated and 61 DEPs were downregulated. Based on Kyoto Encyclopedia of Genes and Genomes (