Objective To compare the safety and efficacy of argatroban and plasmin in the treatment of patients with acute ischemic stroke (AIS). Methods A total of 168 patients with AIS who were not eligible for intravenous thrombolysis within 48 hours of onset were randomly divided into argatroban group and plasmin group. The former was given intravenous infusion of Argatroban injection for 7 days on the basis of conventional antiplatelet therapy; the latter was given intravenous infusion of plasmin for 10 days on the basis of conventional antiplatelet therapy. The National Institutes of Health Stroke Scale (NHISS) score and the modified Rankin (mRS) score at 3-month follow-up were evaluated before treatment and 1 week after treatment to understand the changes of neurological function and prognosis. At the same time, cranial CT/MRI, blood biochemistry, coagulation and other examinations before and after treatment were performed to exclude adverse events (including symptomatic intracranial hemorrhage and other organ hemorrhage). Results The NHISS scores of the AIS patients in the argatroban group and plasmin group were significantly decreased after 1 week of treatment compared with those before treatment (P<0.01); the mRS was significantly decreased after 3 months of follow-up (P<0.05). The total clinical effective rate in the argatroban group was significantly higher than that in the plasmin group after 1 week of treatment (P<0.05). After 1 week treatment of the two groups, the re-examination of cranial CT and biochemical test indicators showed that there were no adverse events (P>0.05). Conclusion Early application of argatroban and plasmin in AIS patients can improve neurological deficits, and the two groups do not increase the occurrence of adverse events, and the clinical efficacy of argatroban is better.