Background: The efficacy of tenecteplase for acute ischemic stroke (AIS) beyond 4.5 h remains uncertain, particularly across care pathways with and without endovascular thrombectomy (EVT). We performed an updated systematic review and meta-analysis using an EVT-stratified framework. Methods: PubMed, Embase, Scopus, and the Cochrane Library were searched through February 2026 for randomized controlled trials comparing tenecteplase with control in imaging-selected patients with AIS presenting 4.5–24 h from last known well. The primary outcome was excellent functional outcome (mRS 0–1) at 90 days. Secondary outcomes were good functional outcome (mRS 0–2), recanalization, early neurological improvement, symptomatic intracranial hemorrhage, and 90-day mortality. Random-effects models with Hartung–Knapp adjustment were used. Subgroup analyses by EVT availability were interpreted as exploratory because of the limited number of trials. Results: Five trials including 1844 patients were analyzed. Tenecteplase improved excellent functional outcome (RR 1.25, 95% CI 1.10–1.42; p = 0.0005) with no heterogeneity (I² = 0%) and no interaction by EVT status (p-interaction = 0.961). Good functional outcome was not significantly different overall (RR 1.10, 95% CI 0.97–1.24; p = 0.135). Significant subgroup interactions were observed for recanalization (p-interaction = 0.004) and early neurological improvement (p-interaction = 0.002), with benefits concentrated in non-EVT settings. However, the larger effect on recanalization did not translate proportionally into functional recovery, supporting separation of vessel-opening outcomes from patient-centered outcomes. Symptomatic intracranial hemorrhage showed a nonsignificant increase in four estimable studies (RR 1.88, 95% CI 0.94–3.78; p = 0.074), whereas 90-day mortality did not differ significantly (RR 1.11, 95% CI 0.85–1.43; p = 0.43). Conclusions: In imaging-selected AIS presenting 4.5–24 h after onset, tenecteplase improved excellent functional outcome irrespective of EVT availability, while benefits for recanalization and early neurological improvement were largely confined to non-EVT settings. Because recanalization is an intermediate endpoint, these findings should not be interpreted as proof of a proportional clinical benefit. Future extended-window trials should specify EVT status.

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