Objective To investigate the effects of the combination of aspirin and nimodipine preconditioning on the prognosis of cerebral ischemia-reperfusion.  Methods Eighty healthy male SD rats were randomly divided into sham group, model group, aspirin preconditioning group and aspirin + nimodipine preconditioning group, with 20 rats in each group. The model of cerebral ischemia reperfusion was established. The rats in each group were given intragastric administration for 5 days before the model was established, and the drug was administered daily for 5 days. Sham group and model group were given normal saline; Aspirin preconditioning group was given 50 mg/kg aspirin; Aspirin + nimodipine preconditioning group was given 50 mg/kg aspirin and 10 mg/kg nimodipine. After 2 hours ischemia and 24 hours reperfusion, the animals were neurologically assessed, and then the volume of cerebral infarction was measured by TTC staining. The contents of superoxide dismutase (SOD), malondialdehyde (MDA), thromboxane B2, 6-keto-prostaglandin-1α in brain tissue were determined by ELISA. The mRNA expression of Notch1, Jagged1 and Hes1 in the brain tissues were detected by Real-time PCR, and the expressions of Jagged1 and Hes1, a downstream substance in Notch signaling pathway, were detected by Western blotting.  Results The neurological deficit score of the aspirin+nimodipine pretreatment group was significantly lower than model group (P<0.05), and the cerebral infarction volume was significantly smaller than other groups. The SOD and 6-keto-prostaglandin 1 in the aspirin pretreatment group and the aspirin plus nimodipine pretreatment group were significantly higher than those in the model group, and the expressions of MDA, thromboxane B2 and thromboxane B2/6-keto-prostaglandin 1 were low. In the model group, the changes in the aspirin + nimodipine pretreatment group were more significant (P<0.05). The expression levels of Notch1, Jagged1 and Hes1 mRNA and protein in the aspirin pretreatment group and aspirin+nimodipine pretreatment group were significantly lower than those in the model group (P<0.05), and the expression level of aspirin+nimodipine pretreatment group was lower than that of aspirin pretreatment group (P<0.05).  Conclusion The protective effect of aspirin plus nimodipine is superior to aspirin alone, which can significantly improve cerebral ischemia-reperfusion injury in rats, which may be exerted through influencing notch signaling pathway to achieve brain tissue protection.