The anticoagulant application is an effective treatment modality for cardiovascular diseases such as coronary heart disease, unstable angina pectoris, and myocardial infarction. In this study, the antithrombotic effect of recombinant neorudin (EPR-hirudin, EH) was evaluated using a canine model of coronary artery thrombosis. A canine model with platelet thrombosis in the left circumferent branch of the coronary artery was designed using Folt’s method, and the anti-thrombus activity of EH was investigated. Femoral administration of EH intravenously had a significant dose-dependent inhibitory effect on canine coronary artery thrombosis and the effective rates were 66.7% (P < 0.05), 83.3% (P < 0.05), and 100% (P < 0.01) after injection of 0.3, 1.0, and 3.0 mg/kg EH, respectively. Furthermore, EH demonstrated lower bleeding, with shorter bleeding time and less bleeding loss than low molecular weight heparin (LMWH). Under the similar effect intensity of EH and LMWH (85 IU/kg), the bleeding time of the EH group at 30 min was shorter, and the blood loss at 30–120 min was less than that of LMWH (P<0.05 and P<0.05–0.001, respectively). EH had a significant dose-dependent inhibitory effect in the dose range of 0.3–3.0 mg/kg on the coronary artery thrombosis and lower bleeding side effects than LMWH with a similar antithrombosis effect.