Background and Purpose: Accumulating evidence from randomized controlled clinical trials suggests that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke. In the present systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for acute ischemic stroke patients with large vessel occlusions (LVOs). Methods: We searched MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus for published randomized controlled clinical trials providing outcomes of acute ischemic stroke with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at a standard dose of 0.9 mg/kg. The primary outcome was the odds of modified Rankin Scale score of 0 to 2 at 3 months. Results: We included 4 randomized controlled clinical trials including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of modified Rankin Scale scores of 0 to 2 (odds ratio, 2.06 [95% CI, 1.15–3.69]), successful recanalization (odds ratio, 3.05 [95% CI, 1.73–5.40]), and functional improvement defined as 1-point decrease across all modified Rankin Scale grades (common odds ratio, 1.84 [95% CI, 1.18–2.87]) at 3 months compared with patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I ² ≤20%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage, any intracranial hemorrhage, and the rates of modified Rankin Scale score 0 to 1 or all-cause mortality at 3 months was detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase. Conclusions: Acute ischemic stroke patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared with patients receiving intravenous alteplase.