To investigate the safety and efficacy of sequential tirofiban combined with colloid volume expansion therapy after intravenous thrombolysis in patients with acute ischemic stroke. Methods: A total of 160 patients with acute ischemic stroke admitted to Xuzhou Central Hospital from January 2021 to June 2023 were selected as the research subjects and were randomly divided into the experimental group and the control group. Cases in the control group (n=80) were given thrombolytic treatment with alteplase only, and cases in the experimental group (n=80) were treated with sequential tirofiban combined with colloid volume expansion therapy on top of the control group’s treatment for a course of 48 hours. Subsequently, both groups were continued with antiplatelet aggregation therapy. The occurrence of adverse events such as bleeding and thrombocytopenia was observed to evaluate the safety in both groups; the degree of neurological deficit was assessed using the National Institutes of Health Stroke Scale (NIHSS) score, and the recovery of neurological function was evaluated using the modified Rankin Scale (mRS) score. Result: From thrombolysis to day 10, there was no significant difference in the incidence of thrombocytopenia between the two groups (P>0.05). From thrombolysis to day 3, there was no significant difference in the incidence of severe and minor bleeding between the two groups (P>0.05). At 7, 14, and 30 days after thrombolytic therapy, the experimental group had lower NIHSS scores than the control group (P<0.05); at 14 and 30 days after treatment, the experimental group showed better therapeutic effects than the control group (P<0.05); at 14, 30, and 90 days after treatment, the experimental group had lower mRS scores than the control group (P<0.05). Conclusion: Sequential tirofiban combined with colloid volume expansion therapy following thrombolysis in acute ischemic stroke patients is safe and effective, improving neurological outcomes and reducing mortality and disability rates.