AIM: To investigate the neuroprotective effect of ginsenoside Rg1 on rats with ischemic stroke and to investigate its mechanism of action. METHODS: Eighty-four SPF-grade SD male rats at about 13 weeks of age were randomly divided into 7 groups (n=12): sham-operated group, model group, Rg1 low-dose group, Rg1 medium-dose group, Rg1 high-dose group, Epac1 agonist group, and Epac1 inhibitor group. The model group, Rg1 low, medium and high dose groups, Epac1 agonist group and Epac1 inhibitor group were all used to establish a permanent focal cerebral ischemia rat model. Rats in the Rg1 low, medium and high dose groups were treated with 60, 120 and 240 μmol/L Rg1 administered by gavage at a fixed time every morning. The rats in the Epac1 agonist and Epac1 inhibitor groups were administered intraperitoneally at a fixed time each morning with a concentration of 1.0×104 μmol/L for the Epac1 agonist 8-CPT and 1.0×105 μmol/L for the inhibitor ESI-09. After two weeks of continuous administration, the rats in each group were decapitated. The brain infarct volume, number of intact neurons, oxidative damage index, apoptosis, and protein expression levels of NOX2, Epac1, Rap1, and caspase3 in each group of rats were detected by TTC staining, Nissler staining, TUNEL staining, microenzyme labeling, and Western blotting method, respectively. RESULTS: Compared with the sham-operated group, the brain infarct volume of rats in the model group and Epac1 agonist group was significantly larger, the number of intact neurons in brain tissue was significantly reduced, the oxidative damage of neurons in brain tissue was significantly aggravated, the apoptosis rate of neuronal cells was significantly higher, and the expression of NOX2, Epac1, Rap1, and caspase3 was significantly higher, with statistically significant differences (P<0.05); compared with the model group, the brain infarct volume was significantly reduced in the Rg1 low, medium and high dose groups and Epac1 inhibitor group, the number of intact neurons in brain tissue was significantly increased, the apoptosis rate of neuronal cells was significantly reduced, and the expression of NOX2, Epac1, Rap1 and Caspase3 was significantly reduced, and the differences were statistically significant (P<0.05). CONCLUSION: Ginsenoside Rg1 can regulate the Epac1/Rap1 signaling pathway after ischemic stroke and attenuate the oxidative stress of brain neurons, thus reducing neurological impairment and exerting a protective effect on neuronal cells.