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Sepsis-induced encephalopathy (SAE) is a detrimental complication in patients with severe sepsis, while there is still no effective treatment. Previous studies have elucidated the neuroprotective effects of glucagon-like peptide-1 receptor (GLP-1R) agonists. However, the role of GLP-1R agonists in the pathological process of SAE is unclear. Here, we found that GLP-1R was up-regulated in the microglia of septic mice. The activation of GLP-1R with Liraglutide could inhibit endoplasmic reticulum stress (ER stress) and associated inflammatory response as well as apoptosis triggered by LPS or tunicamycin (TM) in BV2 cells. In vivo experiments confirmed the benefits of Liraglutide in the regulation of microglial activation, ER stress, inflammation, and apoptosis in the hippocampus of septic mice. Additionally, the survival rate and cognitive dysfunction of septic mice were also improved after Liraglutide administration. Mechanically, cAMP/PKA/CREB signaling is involved in the protection of ER stress-induced inflammation and apoptosis in cultured microglial cells under LPS or TM stimulations. In conclusion, we speculated that GLP-1/GLP-1R activation in microglia might be a potential therapeutic target for the treatment of SAE. Graphic abstract illustrating the mechanism of GLP-1R activation in microglia in the protection against SAE-induced ER stress and associated signaling. Sepsis triggers ER stress and associated inflammation as well as apoptosis in microglial cells. GLP-1R activated by GLP-1R agonist could reverse ER stress and related downstream processes through cAMP/PKA/CREB pathway. [Display omitted] • GLP-1R is mainly expressed in microglia of septic mice. • Activation of GLP-1R on microglia alleviates ER stress and associated apoptosis and inflammation via cAMP/PKA/CREB pathway. • Activation of GLP-1R on microglia improves survival rate and cognitive impairment of septic mice. [ABSTRACT FROM AUTHOR]