To explore the efficacy and safety of recombinant tissue plasminogen activator (rt-PA) and Tenecteplase (TNK) in bridging therapy for acute ischemic stroke patients with large vessel occlusion (LVO). Methods: Baseline data and clinical data of LVO patients (n=104) who underwent bridging treatment in Xuzhou Central Hospital from September 2022 to September 2024 were retrospectively collected. They were divided into two groups based on the difference of intravenous thrombolytic drugs, the TNK group (n=49) and the rt-PA group (n=55). The baseline data, primary and secondary efficacy indicators, and safety indicators of the two groups were statistically analyzed. The primary efficacy indicator referred to the 90 days modified Rankin scale (mRS) score (mRS≤2 was good prognosis, mRS>2 was bad prognosis), and the secondary efficacy indicator referred to the postoperative vascular reperfusion rate and the incidence of early neurological function improvement. Safety indicator included 90 days mortality, incidence of symptomatic intracranial hemorrhage, and incidence of hemorrhage from any site. According to the difference of 90 d mRS scores, patients were divided into good prognosis (n=44) and poor prognosis (n=60) groups, and the factors affecting the prognosis of bridging treatment in LVO patients were screened by using univariate and multivariate logistic regression analyses. Results: The successful reperfusion rate, incidence of early neurological function improvement, 90 days mortality rate, symptomatic intracranial hemorrhage, and hemorrhage from any site were not significantly different between the two groups (all P>0.05). The incidence of good 90 days prognosis of patients in the TNK group was higher than that in the rt-PA group (P<0.05). High NIHSS scores on upon admission was an independent risk factor for poor prognosis in LVO patients and TNK reduces the risk of poor prognosis. Conclusion: The use of TNK before thrombolysis is associated with a better functional prognosis in LVO patients with bridging.