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Abstract Thromboembolic diseases are a significant cause of mortality and are clinically treated enzymatically with tissue plasminogen activator (tPA). Interestingly, prior studies in fibrin fibers and fibrin gels have demonstrated that thrombolysis may be mechanically sensitive. This study aims to expand mechano‐lytic studies to whole blood clots. Furthermore, this study investigates not only how mechanics impacts lysis but also how lysis impacts mechanics. Therefore, clots made from whole human blood are exposed to tPA while the clots are either stretched or unstretched. After, the resulting degree of clot lysis is measured by weighing the clots and by measuring the concentration of D‐dimer in the surrounding bath. Additionally, each clot's mechanical properties are measured. This study finds that mechanical stretch accelerates loss in clot weight but does not impact the lysis rate as measured by D‐dimer. Moreover, lysis not only removes clot volume but also reduces the remaining clot's stiffness and toughness. In summary, tPA‐induced lysis of whole clot appears mechanically insensitive, but stretch reduces clot weight. Furthermore, results show that thrombolysis weakens clot. This suggests that thrombolysis may increase the risk of secondary embolizations but may also ease clot removal during thrombectomy, for example.