To explore the neuroprotective effects and potential mechanism of liraglutide on diabetic rats with ischemic brain injury. Methods: A total of 36 rats were randomly divided into the sham operation group (Sham group), diabetes mellitus and middle cerebral artery occlusion group (DM+MCAO group), and liraglutide treatment group (Liraglutide group). One week after establishing the diabetes mellitus model, each group was given its corresponding treatment for 1 week, and a cerebral ischemia (MCAO) model was then created. Twenty-four hours after development of the MCAO model, neurological behavior was evaluated by neurological deficit scores; infarct volume was analyzed with TTC staining; expression of TLR4 and Myd88 proteins was measured by Western Blotting; expression of NF-κB p65 mRNA was detected by real-time PCR; and concentrations of IL-1β and TNF-α were measured by ELISA. Results: Blood glucose of the DM+MCAO and Liraglutide groups significantly increased 1 week after injection of STZ (P<0.05), and blood glucose of the Liraglutide group significantly decreased 1 week after injection of liraglutide (P<0.05). Compared with that of the DM+MCAO group, the neurological deficit scores and infarct volume of the Liraglutide group significantly declined (P<0.05), protein expression of TLR4 and Myd88 significantly decreased (P<0.05), mRNA expression of NF-κB p65 significantly decreased (P<0.05), and concentrations of IL-1β and TNF-α significantly decreased (P< 0.05). Conclusion: Our data indicate that the liraglutide exerts neuroprotective effects on diabetic rats with ischemic brain injury possibly through inhibiting the inflammatory response mediated by the TLR4/Myd88 signal pathway.