To explore the mechanism of Icariin fights cerebral ischemia reperfusion injury in rats based on molecular docking and experiments.Molecular docking simulations have delineated the binding affinity of icariin with SIRT1 and interleukin-6 (IL-6).The rat of cerebral ischemia reperfusion injury model (MCAO) was replicated by line embolism method. Then the successful creation of the mold was divided into the model group, high dose group (80 mg/kg), medium dose group (40 mg/kg), low dose group (20 mg/kg), EX527 group (5 mg/kg) and high dose +EX527 group. The medication was administered intragastrically as a single dose at 24 hour, 48 hour, and 72 hour intervals(EX527 was injected intraperitoneally). Neural function score was performed. TTC staining was used to measure cerebral infarction rate. HE staining was used to observe the damage of cortical neurons, relevant indexes IL-6 and IL-1β were detected by enzyme-linked immunosorbent assay, and SIRT1 fluorescence expression was detected by immunofluorescence staining.Molecular docking results demonstrated that Icariin exhibits stable binding affinity to both IL-6 and SIRT1. Compared with the sham operation group, the experimental study showed that the neural function score of the model group was increased in the model group, the cerebral infarction volume was enlarged in the model group, The pathological lesions affecting the cerebral cortex on the ischemic hemisphere were severe in the model group, the levels of serum related inflammatory indicators IL-6 and IL-1β were increased, Immunofluorescence staining revealed a marked decrement in SIRT1 protein expression within the model group. Compared with the model group, Notably, the neurofunctional state of Icariin was significantly enhanced across the Icariin of low, medium and high dosing groups,the cerebral infarction volume was narrowed in the Icariin of low, medium and high dosing groups. The pathological lesions affecting the cerebral cortex on the ischemic hemisphere were alleviated in the Icariin of low, medium and high dosing groups, the levels of serum related inflammatory indicators IL-6 and IL-1β were decreased. Immunofluorescence staining revealed a marked augment in SIRT1 protein expression within the Icariin of low, medium and high dosing groups. Compared with the high dose of Icariin group, immunofluorescence staining revealed a marked decrement in SIRT1 protein expression within the high dose of Icariin group +EX527. Compared with the EX527 group, immunofluorescence staining revealed a marked increment in SIRT1 protein expression within the high dose of Icariin group +EX527. Icariin may inhibit cerebral ischemia reperfusion injury by activating SIRT1 signaling pathway.