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Introduction Patients with acute vertebrobasilar artery occlusion (VBAO) and large-core infarction (posterior circulation ASPECTS [pc-ASPECTS] ≤6) were largely excluded from thrombectomy trials, leaving the benefit of endovascular therapy (EVT) uncertain. We evaluated the safety and efficacy of EVT versus best medical management (BMM).Materials and Methods We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines (PROSPERO registration CRD420251148495). PubMed, Embase, and the Cochrane were searched from inception through September 2025. Eligible studies were full-text comparative cohorts of adults with VBAO and pc-ASPECTS ≤6 treated within 24 hours of stroke symptom onset, reporting outcomes at 90-day following EVT or BMM. Outcomes were 90-day modified Rankin Scale (mRS) 0-2 and 0-3, symptomatic intracranial hemorrhage (sICH), and mortality. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using random-effects models, and heterogeneity was quantified with I 2.Results Four studies comprising 1,234 patients (EVT, 709; BMM, 525) were included. Baseline stroke severity was high (median NIHSS 16-36). EVT was associated with higher rates of 90-day functional independence (mRS 0-2: RR 1.54; 95% CI 1.35-1.74; I 2 = 0%) and a higher likelihood of a favorable outcome (mRS 0-3: RR 1.64; 95% CI 1.37-1.97; I2 = 0%). Mortality did not differ significantly between EVT and BMM (RR 0.77; 95% CI 0.57-1.03; I2 = 65%). Rates of sICH were also not significantly different (RR 1.54; 95% CI 0.56-4.40; I2 = 8%). Heterogeneity was minimal for functional outcomes and moderate-to-high for mortality. In leave-one-out analyses, exclusion of any single study did not change the direction of the pooled associations.Conclusion Among adults with VBAO and pc-ASPECTS ≤6, EVT was associated with improved 90-day functional outcomes without increased risk of sICH or mortality. Prospective studies are needed to clarify the benefit of EVT in this high-risk subgroup using prespecified imaging selection.Disclosures P. Vega-Medina: None. R. Tatit: None. F. Colella: None. A. González-Chang: None. L. Cosmo: None. A. Precilla-Ettrick: None. S. Cuervo: None. J. Vera: None. G. Chevasco-Champsaur: None. H. Iyer: None. M. Lin: None. R. Tawk: None.