Objective This experiment was conducted to study the effect of safflower injection on the expression of ER stress-related molecules, GRP78, CHOP, and high-sensitivity C-reactive protein in the brain of rats with middle cerebral artery occlusion(MCAO),to explore the effect of safflower injection on the treatment of stroke by modulating inflammation through ERS, so as to provide an experimental basis for the clinical application of safflower injection in the treatment of acute cerebral infarction. Methods A rat MCAO model was established through a modified suture method,followed by intravenous injection of safflower. Rat brain tissues were examined by immunohistochemistry to determine the expression of ERS-related markers CHOP and GRP78. RT-qPCR was performed to determine the expression of GRP78 mRNA and CHOP mRNA. ELISA was used to determine the expression level of high-sensitive C-reactive protein. Results Twelve hours after stroke, the cerebral infarction area ratio of the safflower injection group was significantly lower than that of the model group. The neurological deficit scores of the safflower injection group were significantly lower than those of the model group. The expression of GRP78-positive cells in the safflower injection group was significantly higher than that of the model group, while the expression of CHOP in the safflower injection group was significantly lower than that of the model group. Compared with that in the model group, there was no significant difference in the expression of GRP78 mRNA and CHOP mRNA in the safflower injection group. The CRP content of the safflower injection group was significantly lower than that of the model group. Conclusions Safflower injection has protective effects against stroke, and the mechanism of ERSrelated to CRP may be mediated by upregulation of GRP78 and downregulation of CHOP.