Objective To investigate the antithrombotic effects and relevant mechanisms of Dange Huoxue Huayu Granules on mice. Methods Kunming mice were randomly divided into blank control group, model group (collagen⁃epinephrine⁃induced acute pulmonary thrombosis model or carrageenan⁃induced tail thrombosis model), positive drug control group (aspirin in 0.03 g/kg), and low⁃dose (3.75 g/kg), medium⁃dose (7.50 g/kg), and high⁃dose (15.00 g/kg) Dange Huoxue Huayu Granules groups. After intragastric administration of the corresponding drugs (the blank control group received intragastric administration of an equal volume of distilled water), the antithrombotic effects of Dange Huoxue Huayu Granules on mice were observed using the mouse bleeding time test, mouse clotting time test, collagen⁃epinephrine⁃induced acute pulmonary thrombosis test in mice, and carrageenan⁃induced tail thrombosis test in mice. Results Compared with the blank control group, the bleeding time was prolonged in the high⁃dose Dange Huoxue Huayu Granules group and the positive drug control group, and the clotting time was prolonged in the positive drug control group and the low⁃dose, medium⁃dose, and high⁃dose Dange Huoxue Huayu Granules groups (P<0.05). The protective rates in the high⁃dose Dange Huoxue Huayu Granules group and the positive drug control group were higher than those in the model group (P<0.05). Except for the blank control group, mice in the remaining groups developed dark red thrombi of varying degrees in their tails. Compared with the model group, the relative black tail length was reduced in the high⁃dose Dange Huoxue Huayu Granules group and the positive drug control group (P<0.05). Compared with the blank control group, the model group showed shortened prothrombin time (PT) and activated partial thromboplastin time (APTT), increased fibrinogen (FIB), elevated plasma contents of tumor necrosis factor α (TNF⁃α), interleukin 1β (IL⁃1β), and plasminogen activator inhibitor 1 (PAI⁃1), and decreased plasma tissue⁃type plasminogen activator (t⁃PA) content (P<0.05). Compared with the model group, the high⁃dose Dange Huoxue Huayu Granules group exhibited prolonged PT and APTT, decreased FIB, reduced plasma contents of TNF⁃α, IL⁃1β, and PAI⁃1, and increased plasma t⁃PA content; in addition, the positive drug control group showed prolonged APTT, reduced plasma contents of TNF⁃α, IL⁃1β, and PAI⁃1, and increased plasma t⁃PA content (P<0.05). Conclusion Dange Huoxue Huayu Granules possess antithrombotic effects to a certain extent, which may be related to improving coagulation function, inhibiting blood platelet function, suppressing inflammatory cytokine release, and enhancing fibrinolysis.