Objective To investigate the effect of propofol on the protein kinase A ( PKA) / cyclic adenosine monophosphate response element binding protein (CREB) pathway and the improvement of neurological function in focal cerebral ischemia-reperfusion injury (CIRI) rats. Methods A CIRI model was established in rats by modified thread occlusion and ischemia for 2 hours and reperfusion for 24 hours. The rats were randomly divided into model group (CIRI group), propofol low-dose , middle-dose , high-dose group ( 10, 25, 50 mg / kg), with 12 rats in each group. A sham group was prepared without inserting wires. The drug was administered only after the model was successfully established and was administered once a day for 4 weeks. Twelve hours after the last administration, modified neurological severity scores (mNSS) were used to evaluate neurological deficit. The rats were then killed and brains dissected out. The cerebral infarction volume was measured using 2,3,5-triphenyltetrazoliumchloride ( TTC) staining. Hematoxylin Eosin and Nissl staining were used to observe the morphological changes of neurons and Nissl bodies; TUNEL ( terminal deoxynucleotidyl transferase dUTP nick end labeling) staining was used to reveal neuronal apoptosis, and the relative expression levels of PKA, CREB and brain derived neurotrophic factor (BDNF) were detected by western blotting. Results Compared with the sham group, the mNSS score, cerebral infarction volume, degree of pathological damage to the cerebral cortex, degeneration index of nerve cells, and apoptosis rate were all increased ( P< 0. 05), and the protein levels of PKA, pCREB, and BNDF were decreased (P< 0. 05) in the CIRI group. Compared with the CIRI group, the mNSS score, cerebral infarction volume, degree of pathological damage to the cerebral cortex, degeneration index of nerve cells, and apoptosis rate decreased in a dose-dependent manner (P< 0.05), and the protein levels of PKA, pCREB, and BNDF increased in a dose-dependent manner (P< 0.05) in the low-, middle- and high-dose propofol groups Conclusions Propofol can activate expression of PKA/ CREB/ BNDF pathway proteins in the cortex, reduce the cerebral infarct volume, and reduce neurological damage in CIRI rats.