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Background and Purpose: Cancer cachexia and cancer‐associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non‐small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown. Experimental Approach Clinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r‐hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r‐hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined. Key Results: Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r‐hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR‐1‐deficient NSCLC cells. r‐hirudin and DTIP inhibited tumour progression through the thrombin‐PAR‐1‐mediated RhoA and NF‐κB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy‐induced growth and metastatic inhibition and inhibited chemotherapy‐induced resistance in mice. Conclusions and Implications: Thrombin makes a substantial contribution, together with PAR‐1, to NSCLC malignancy. The anti‐coagulants, r‐hirudin and DTIP, could be used in anti‐tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects. [ABSTRACT FROM AUTHOR]