To investigate the application value of four novel thrombotic molecular markers (TAT, TM, t-PAIC, PIC) combined with the venous thromboembolism (VTE) risk assessment scale in the treatment of patients with VTE, a total of 100 patients with a VTE score ≥ 3 in Baoding No.2 Hospital from May 2022 to April 2025 and 30 healthy subjects (control group) were enrolled. Patients diagnosed with deep vein thrombosis (DVT) were randomly divided into Observation Group 1 (anticoagulant therapy) and Observation Group 2 (anticoagulant plus thrombolytic therapy). Thrombotic markers were compared among groups, and dynamic changes of markers at different time points were evaluated between the two treatment groups. The results show that TM, PIC, and TAT levels in the VTE ≥ 3 group are significantly higher than those in the control group (P<0.05), while there is no significant difference in t-PAIC (P> 0.05). All thrombotic markers changes significantly over time (P< 0.001), and both treatment regimens improved thrombotic status. In Observation Group 2, t-PAIC increases significantly within 24 hours after treatment, and PIC remains relatively high at 1 week after treatment (P< 0.05). TM exhibits a significant time × group interaction effect (P< 0.001). In conclusion, novel thrombotic molecular markers combined with the VTE risk assessment scale can effectively evaluate the risk of venous thrombosis and dynamically monitor therapeutic efficacy, providing a basis for clinical decision-making. Moreover, anticoagulant plus thrombolytic therapy achieves a better therapeutic effect.