Abstract Background The benefits and risks of tenecteplase (TNK) versus alteplase (ALT) have recently been assessed in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT) with diverse results. Due to its high fibrin specificity and lack of excitotoxicity, TNK may have a higher efficacy and safety profile. This study aimed to evaluate the benefits and risks of TNK compared to ALT in AIS patients prior to thrombectomy. Methods We systematically searched four key databases, PubMed, Embase, Web of Science and Cochrane Library until January 27, 2024 for clinical studies evaluating the effects of TNK versus ALT in patients with large vessel occlusion undergoing MT. A random-effect meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Ten studies involving 3722 patients receiving TNK (1266 patients) or ALT (2456 patients) were included (age: 69.05 ± 14.95 years; 55.64% male). Compared to ALT-treated patients, TNK-treated patients demonstrated significantly higher rates of early recanalization (odds ratio 2.02, 95%-confidence interval 1.20–3.38, p = 0.008) without increased risk of symptomatic intracerebral hemorrhage (1.06, 0.64–1.76, p = 0.82) or intracerebral hemorrhage (1.21, 0.66–2.25, p = 0.54). TNK-treated patients showed similar rates of functional independence at 90 days (1.13, 0.87–1.46, p = 0.37) as ALT-treated patients, but lower rates of mortality within 90 days (0.65, 0.44–0.96, p = 0.03). Conclusion TNK is superior to ALT in achieving early recanalization and is associated with lower mortality within 90 days in AIS patients undergoing MT. Compared with ALT, TNK does not significantly alter functional independence at 90 days, symptomatic intracerebral hemorrhage or intracerebral hemorrhage.