BackgroundDespite the success of endovascular thrombectomy (EVT) in restoring large-vessel patency in acute ischemic stroke (AIS), a substantial proportion of patients fail to achieve functional independence, largely due to ischemia-reperfusion injury (IRI) at the tissue level. Pharmacological neuroprotection has re-emerged as a potential strategy to mitigate these downstream injury cascades in the thrombectomy era; however, clinical evidence remains heterogeneous and mechanism-specific effects are unclear.MethodsWe performed a systematic review and meta-analysis of randomized controlled trials evaluating neuroprotective pharmacotherapies administered as adjuncts to EVT in AIS. PubMed, Embase, and the Cochrane Library were searched from inception to 31 January 2026. The primary outcome was functional independence at 90 days (mRS 0–2). Random-effects models were used for pairwise meta-analysis, with an exploratory network meta-analysis (NMA) performed as a secondary, hypothesis-generating analysis.ResultsNine RCTs involving 4,420 patients were included. Adjunctive neuroprotective therapy was associated with a modest increase in functional independence compared with control (OR 1.13, 95% CI 1.01–1.28). However, most secondary efficacy outcomes did not show clear statistically significant benefits, and no significant differences were observed in mortality, symptomatic intracranial hemorrhage, or serious adverse events. Exploratory subgroup analyses suggested possible effect modification by treatment timing and reperfusion context, while the exploratory NMA indicated heterogeneous treatment rankings. These findings should be interpreted as a modest and heterogeneous efficacy signal rather than definitive evidence that neuroprotection is effective as a general therapeutic class.ConclusionIn the thrombectomy era, adjunctive pharmacological neuroprotection may provide a modest field-level signal of potential benefit without clear evidence of increased major safety risks. However, given the heterogeneity in pharmacological mechanisms, treatment timing, and reperfusion contexts, these findings should not be interpreted as definitive evidence of efficacy for neuroprotection as a general therapeutic class. Future mechanism-informed trials are needed to determine which neuroprotective approaches, if any, provide clinically meaningful benefit in AIS. This study was prospectively registered in PROSPERO (CRD420261284814).Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420261284814, identifier PROSPERO (CRD420261284814)