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Introduction: Acute ischemic stroke (AIS) is a leading cause of mortality and long-term disability worldwide. Tenecteplase, a genetically modified tissue plasminogen activator (tPA), presents distinct pharmacokinetic advantages and a more simplified administration protocol compared to alteplase. In March 2025, the US-FDA approved Tenecteplase for AIS treatment, demonstrating non-inferiority to alteplase in both safety and efficacy. Methods: A systematic search of MEDLINE, EMBASE, CENTRAL and SCOPUS was conducted up to August 2025 for Randomized Control Trials (RCTS). Meta-analysis was performed using Stata 18.0, and ROBS 2.0 assessed the risk of bias. Results: A total of 2,896 studies were screened, with 18 meeting the inclusion criteria, involving 11,347 patients (1,710 Tenecteplase, 6,841 Alteplase, and 3,068 controls). Tenecteplase demonstrated significantly better survival outcomes (OR = 0.07, 95% CI: 0.02, 0.12), indicating lower risk of mortality compared to Alteplase (OR = 0.49, 95% CI: 0.21, 0.78). In Symptomatic cranial hemorrhage, both treatments demonstrated no significant differences, with Tenecteplase showing an OR of 0.12 (95% CI: -0.29, 0.54) and Alteplase an OR of 0.88 (95% CI: -0.24, 1.86). Tenecteplase showed a moderate effect on the modified Rankin scale with an OR of 0.48 (95% CI: -0.37, 1.32), while Alteplase demonstrated a significant improvement (OR = 0.27, 95% CI: 0.11, 0.65). The Barthel Index also favored Alteplase, with an OR of 0.48 (95% CI: 0.37, 1.32), compared to Tenecteplase's OR of 0.24 (95% CI: -0.27, 0.76). Both treatments show similar effects on SCIH. Tenecteplase and Alteplase show different risk ratios (RR) for adverse outcomes. For infections, both treatments showed no significant difference in risk, with Tenecteplase at RR 0.35 (95% CI: -0.81, 1.51) and Alteplase at RR 0.16 (95% CI: -0.75, 0.42). Tenecteplase had a higher RR for injection site reactions (ISR) at 0.63 (95% CI: 0.42, 1.62), compared to Alteplase’s 0.47 (95% CI: 0.25, 0.53). For adverse events overall, Tenecteplase had a higher RR of 0.24 (95% CI: 0.14, 0.31), indicating more frequent adverse events than Alteplase (RR 0.17, 95% CI: 0.08, 2.1). Conclusion: Tenecteplase offers better survival outcomes in acute ischemic stroke, while Alteplase provides greater functional recovery. These findings aid clinical decision-making with low risk of bias