Objective: To investigate the application value of rivaroxaban combined with mechanical prophylaxis in primary prevention of venous thromboembolism (VTE) in malignant tumor patients with high Khorana score. Methods: 128 patients with malignant tumors and a high risk of VTE (Khorana score ≥ 2) were selected and divided into three groups according to the intervention plan: namely, the combined prevention group (n = 42, rivaroxaban + mechanical prophylaxis), the rivaroxaban group (n = 43, rivaroxaban), and the mechanical prophylaxis group (n = 43, mechanical prophylaxis), with an intervention period of 6 months. The incidence of VTE, femoral superficial vein diameter (FSV), popliteal vein diameter (POPV), peak velocity (PV), average velocity (MV), plasma viscosity, whole blood high-shear viscosity, activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), D-dimer (D-D), 6-keto-prostaglandin F1α (6-K-PGF1α), endothelin-1 (ET-1), C-reactive protein (CRP), interleukin-6 (IL-6), and the incidence of bleeding events were compared among the three groups. Results: After 6 months of intervention, the incidence of VTE in both the combined prevention group and the rivaroxaban group was lower than that in the mechanical prophylaxis group (P 0.05). Conclusion: Rivaroxaban combined with mechanical prophylaxis can reduce the risk of VTE in malignant tumor patients with high Khorana scores, optimize the structural morphology and hemodynamic status of lower extremity veins, regulate hemorheological characteristics and coagulation function, and reduce the body’s inflammatory response.