Neuroinflammation is closely linked to the pathogenesis of Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) analogs exhibit anti-inflammatory and neuroprotective effects; hence, we investigated whether they reduce cognitive impairment and protect astrocytes from oxidative stress. We found that 5 × FAD transgenic mice treated with the synthetic GLP-1 receptor agonist exenatide had improved cognitive function per the Morris water maze test. Immunohistochemistry, western blotting, and ELISAs used to detect inflammatory factors revealed reduced neuroinflammation in extracted piriform cortexes of exenatide-treated mice as well as lower amyloid β1-42-induced oxidative stress and inflammation in astrocytes treated with exendin-4 (the natural analog of exenatide). Adenovirus-mediated overexpression of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 2 (NLRP2) revealed that exenatide/exendin-4 function may be attributed to NLRP2 inflammasome inhibition. Collectively, our results indicate that GLP-1 analogs improve cognitive dysfunction in vivo and protect astrocytes in vitro, potentially via the downregulation of the NLRP2 inflammasome. •Exenatide reduces amyloid deposition and improves cognition in 5 × FAD mice.•Exenatide reduces astrocyte activation and NLRP2 levels in the piriform cortex.•Exenatide alleviates inflammatory responses in the piriform cortex of 5 × FAD mice.•Exendin-4 improves survival and reduces oxidative stress in astrocytes in vitro.•Exendin-4 mitigates the effects of Aβ- and NLRP2-overexpression in astrocytes.