Background <p>Stroke, a leading cause of morbidity and mortality worldwide, is a cerebrovascular disorder characterized by acute brain injury due to cerebral blood vessel occlusion or rupture. Post-stroke cerebral edema significantly contributes to poor prognosis, yet effective preventive therapies remain limited. Recent studies suggest that glibenclamide exhibits anti-edema and neuroprotective properties in central nervous system (CNS) injuries, showing promise in experimental stroke models.</p> Methods <p>A systematic search of PubMed, Web of Science, Embase, and Scopus was conducted from their inception to April 5, 2025. Search terms included “glibenclamide” combined with “stroke”, “cerebral infarction”, “cerebral hemorrhage”, or “subarachnoid hemorrhage”. A favorable outcome was defined as the modified Rankin Scale (mRS) scores 0–2 at 90 days, which served as the primary outcome. Secondary outcomes included the incidence of hypoglycemia, pneumonia, decompressive craniectomy, cardiac events, mortality, and serious adverse events.</p> Results <p>Seven studies involving a total of 1,225 participants were included. Regarding the primary outcome, no statistically significant difference was observed (odds ratio [OR] = 1.25, 95% confidence interval [CI] 0.92 to 1.70; <i>P</i> = 0.15). For secondary outcomes, glibenclamide treatment was associated with a significantly increased risk of hypoglycemic events (OR = 3.83, 95% CI 1.12 to 13.14; <i>P</i> = 0.03). However, there were no statistically significant differences in the incidence of pneumonia, decompressive craniectomy, cardiac events, mortality, or serious adverse events.</p> Conclusion <p>Current evidence does not support the efficacy of glibenclamide in improving post-stroke neurological function. Furthermore, its administration is associated with an elevated risk of hypoglycemia. Therefore, glibenclamide is not recommended for routine clinical use in this population.</p> Registration number <p>CRD420251024136.</p>