Glucagon-like peptide-1 (GLP-1) is a gut-derived peptide that has various physiological actions. One of its main actions is the regulation of blood glucose level when it is elevated as it potentiates insulin release. It is also known that GLP-1 protects neurons from damage caused by neurodegenerative diseases. Lixisenatide is one of the GLP-1 analogues that has a strong affinity to the GLP-1 receptor. Experimental animal studies have shown that it holds a neuroprotective effect in Parkinson, myocardial, and cerebral ischemic disease animal models. The beneficial effect of lixisenatide on the brain after cerebral ischemia-reperfusion (I/R) is not clarified yet; thus, it needs further explanatory studies. Our research is the first to study the effect of lixisenatide on myeloperoxidase (MPO) and toll-like receptors (TLRs)/mitogen-activated protein kinase (MAPK) pathway in a rat model of cerebral I/R. Lixisenatide with 2 doses 0.7 and 7 nmol/kg was given intraperitoneal in 2 different groups for 14 days; then, the bilateral common carotid artery was occluded for 1 h followed by reperfusion for 1 h. Examination of hippocampus CA1 neurons by Nissl stain showed that the number of intact neurons was elevated in the lixisenatide-treated group related to the control group (I/R group). Lixisenatide exhibited neuroprotection action possibly via downregulation of MPO, TLR2/4, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and pP38 and upregulation of phosphorylated extracellular signal-regulated kinase (pERK1/2); thus, this study gives possible link between lixisenatide and TLR/MAPK pathway following cerebral I/R and supports the use of lixisenatide for neuroprotection against stroke.