INTRODUCTIONAcute ischemic stroke (AIS) is a leading cause of morbidity and mortality worldwide. While alteplase has been widely used for acute management, recent clinical trials suggest that tenecteplase (TNK) may offer improved clinical outcomes. This study aims to compare the efficacy and safety of TNK compared with alteplase.METHODSA comprehensive literature search was conducted using PubMed, Embase and Cochrane Library from inception to October 2024 to identify randomized controlled trials that compared TNK at 0.25 mg/kg dosage with alteplase. Data about clinical outcomes was extracted from both groups and assessed by generating forest plots using the random-effects model and pooling odds ratios (ORs).RESULTSA total of 11 RCTs with 7,546 patients were included in the analysis. TNK showed statistically significant improvement in excellent functional outcome (mRS 0-1) compared with alteplase (OR= 1.14, 95 % CI= 1.03-1.25). No statistically significant difference was observed for good functional outcome (mRS 0-2) (OR= 1.11, 95 % CI= 0.9-1.25), early neurological improvement (OR=1.08, 95 % CI= 0.93-1.26), all-cause death (OR=0.99, 95 % CI= 0.81-1.19), symptomatic intracranial hemorrhage (OR=1.11, 95 % CI=0.81-1.52) and poor functional outcome (mRS=4-6) (OR=0.95, 95 % CI=0.79-1.14).CONCLUSIONIn patients with acute ischemic stroke, TNK demonstrated a significant advantage over alteplase in achieving excellent functional outcomes. The incidence of early neurological improvement, symptomatic intracranial hemorrhage, all-cause death, and poor functional outcome remained comparable across the two groups.