Introduction: Acute ischemic stroke remains the major cause of death and disability and conclusive evidence of Tenecteplase in treating stroke is lacking. Objective: To conduct a meta-analysis to determine whether Tenecteplase produces better outcomes than Alteplase and a network meta-analysis comparing the different dosing regimens of Tenecteplase. Methods: Searches were made in MEDLINE, CENTRAL, and ClinicalTrials.gov. The outcome measures are recanalization, early neurological improvement, functional outcomes at 90 days (modified Rankin Scale 0–1 and 0–2), intracranial hemorrhage, symptomatic intracranial hemorrhage, and mortality within 90 days from treatment. Results: Fourteen studies are included in the meta-analyses and 18 studies in the network meta-analyses. In the meta-analysis, Tenecteplase 0.25 mg/kg has significant results in early neurological improvement (OR = 2.35, and 95% CI = 1.16–4.72) and excellent functional outcome (OR = 1.20, and 95% CI = 1.02–1.42). In the network meta-analysis, Tenecteplase 0.25 mg/kg produces significant results in early neurological improvement (OR = 1.52 [95% CI = 1.13–2.05], p-value = 0.01), functional outcomes (mRS 0–1 and 0–2) (OR = 1.19 [95% CI = 1.03–1.37], p-value = 0.02; OR = 1.21 [95% CI = 1.05–1.39], p-value = 0.01; respectively) and mortality (OR = 0.78 [95% CI = 0.64–0.96], p-value = 0.02) whereas Tenecteplase 0.40 mg/kg increases the chances of symptomatic intracranial hemorrhage (OR = 2.35 [95% CI = 1.19–4.64], p-value = 0.01). Conclusion: While not conclusive, our study lends evidence to 0.25 mg/kg Tenecteplase dose for ischemic stroke treatment. Further randomized trials need to be done to validate this finding. Registration: International prospective register of systematic reviews (PROSPERO) – CRD42022339774 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=339774

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