Zhi-Xiong Capsules (ZXC) involving Hirudo, Ligusticum chuanxiong, Salvia miltiorrhiza, Leonurus artemisia, and Pueraria lobata, is an empirical prescription used in Chinese clinics applied for treating cerebral arteriosclerosis and blood-stasis in clinic. However, the mechanism of its antithrombotic activity has not been investigated until now. The present study was designed to investigate its antithrombotic effects, the mechanism of ZXC on anti-thrombus action and to identify the main chemical composition of ZXC using HPLC-DAD-ESI-IT-TOF-MS. Two animal models were used to evaluate the antithrombotic effect of ZXC, the arterial thrombosis model and a venous thrombosis model. ZXC prolonged the plasma recalcification time (PRT), the activated partial thromboplastin time (APTT), the thrombin time (TT) and the prothrombin time (PT) and clearly reduced the content of fibrinogen (FIB) obviously in the arterial thrombosis model. Furthermore, it markedly suppressed the level of TXB₂ and up-regulated the level of 6-keto-PGF_1a. In addition, it significantly up-regulated the level of t-PA and down-regulated the level of PAI-1 (p < 0.05). These results revealed that ZXC played a vital role in the prevention of thrombosis through interacting with multiple targets, including inhibition of coagulation and platelet aggregation and increasing thrombolysis. A total of 23 compounds were identified as the main components of ZXC by HPLC-DAD-ESI-IT TOF-MS.