Glucagon-like Peptide-1 receptor agonists (GLP-1RA) are gaining increasing momentum as possible neuroprotective agents in acute ischemic stroke. In this study, we investigate the neuroprotective effects of a novel GLP-1RA, Semaglutide, in the treatment of acute ischemic stroke and their underlying mechanisms. The current study first mapped comprehensive proteomic changes after acute ischemic stroke treated with Semaglutide, providing a foundation for developing potentially therapeutic targets for anti-acute ischemic stroke and clinically prognostic biomarkers of stroke.