Objective: To investigate the efficacy, safety, and comparative advantages of intravenous thrombolytic therapy with tenecteplase versus alteplase in the treatment of acute ischemic stroke. Methods: A total of 60 patients with acute ischemic stroke who were admitted to the neurology ward of the hospital within 4.5 hours of onset from 2022 to 2024 were enrolled. Among them, 30 patients in the observation group received intravenous thrombolysis with tenecteplase, while the other 30 patients in the control group received intravenous thrombolysis with alteplase. The clinical efficacy of the two groups was compared. Results: The NIHSS scores of both groups at 1 hour, 24 hours, 72 hours, and 7 days after thrombolysis were lower than those before thrombolysis, and the Barthel index at 90 days after thrombolysis was higher than that before thrombolysis. The overall response rates of the observation group at 1 hour, 24 hours, 72 hours, and 7 days after thrombolysis were higher than those of the control group (P < 0.05). There were no significant differences in the incidence of adverse reactions and mortality between the two groups after thrombolysis (P > 0.05). The observation group had a higher rate of favorable functional outcomes and a higher Barthel index at 90 days after thrombolysis compared to the control group (P < 0.05). Conclusion: Tenecteplase can enhance early neurological function and improve functional outcomes in patients with ischemic stroke without increasing the incidence of adverse reactions.