Objective: To investigate the clinical efficacy and safety of tirofiban arterial thrombolysis combined with sequential intravenous therapy in patients with acute ischemic stroke (AIS). Methods: A total of 85 AIS patients admitted to the hospital from February 2024 to February 2026 were selected as the study subjects. They were divided into a control group (44 cases, treated with tirofiban intravenous therapy alone plus conventional therapy) and an observation group (41 cases, treated with tirofiban arterial thrombolysis combined with sequential intravenous therapy plus conventional therapy) according to the treatment regimen. The National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores of the two groups were compared before treatment and at 1 day, 3 days, 7 days, and 90 days after treatment. The occurrence of adverse reactions during treatment was also recorded. Results: Compared with the control group, the NIHSS scores of the observation group were lower at all time points (1 day, 3 days, 7 days, and 90 days after treatment) (all P < 0.001). At 90 days after treatment, the proportion of patients with an mRS score of 0–2 in the observation group was 78.05%, higher than that in the control group (56.82%). Meanwhile, the proportion of patients with poor prognosis and death in the observation group was 21.95%, lower than that in the control group (43.18%) (P < 0.05). During treatment, there was no statistically significant difference in the incidence of adverse reactions between the observation group and the control group (P > 0.05). Conclusion: Tirofiban arterial thrombolysis combined with sequential intravenous therapy for AIS can effectively improve neurological deficits in patients, enhance long-term prognosis, and does not increase the risk of serious adverse reactions, demonstrating high clinical safety.