AbstractPlatelet glycoprotein (GP) IIb/IIIa antagonists have been employed in selective patients after endovascular therapy (EVT) for acute ischemic stroke (AIS), yet application in patients without EVT is debated. This meta‐analysis of randomized controlled studies on AIS patients without EVT assessed the effectiveness and safety of platelet GP IIb/IIIa antagonists compared with traditional antiplatelet or thrombolysis therapy. Articles were retrieved from databases, including PubMed, Web of Science, EMBASE, and Cochrane. The risk of bias and certainty level of evidence were assessed. Fifteen studies were included. GP IIb/IIIa antagonists increased the proportion of patients with modified Rankin Scale (mRS) 0–1 (odd ratio [OR] 1.37, 95% confidence interval [CI] 1.04–1.81, p = 0.03), mRS 0–2 (OR 1.27, 95% CI 1.12–1.46, p = 0.0004), and Barthel Index (BI) 95–100 (OR 1.25, p = 0.005); decreased the proportion of stroke progression within 5 days (OR 0.66, p = 0.006); and lowered the mean mRS score at 90 days (mean difference [MD] −0.43, p = 0.002) and the National Institute of Health stroke scale score at 7 days (MD −1.64, p < 0.00001) compared with conventional treatment. Proportions of stroke recurrence within 90 days (OR 1.20, p = 0.60), any intracranial hemorrhage (aICH) (OR 1.20, p = 0.12), symptomatic intracranial hemorrhage (sICH) (OR 0.91, p = 0.88), and death (OR 0.87, p = 0.25) had no statistical difference between both groups. This meta‐analysis finds that compared with traditional antiplatelet or thrombolysis therapy, GP IIb/IIIa antagonists administered within 24–96 h of ischemic stroke onset significantly improve functional prognosis of patients with AIS not receiving EVT, as indicated by mRS and BI at 90 days, and do not increase the incidence of aICH, sICH, and death.