Thrombolysis is essential for treating vascular conditions such as pulmonary embolism and deep vein thrombosis, yet current thrombolytic drug-based approaches have notable limitations in efficacy and safety. Hydrodynamic cavitation (HC) offers drug-free clot degradation through mechanical disruption. In this study, the effects of HC exposure on thrombolysis were investigated using a clot-on-a-chip (CoC) platform. In this regard, the thrombolytic potential of HC exposure was evaluated by analyses involving hemolysis and fibrinolysis. Furthermore, the results were compared with acoustic cavitation (AC), a widely studied alternative. According to the obtained results, HC exposure (482 kPa, 120 s) resulted in 12.1% released hemoglobin and a 53.4% reduction in clot mass. In contrast, AC exposure (24 kHz, 50% nominal output power, 30 s) led to a 1.3-fold greater mass reduction with 26.8% released hemoglobin, likely due to additional thermal effects. Morphological analyses revealed that HC treatment significantly reduced red blood cell density in a pressure- and time-dependent manner. Notably, HC treatment effectively eroded blood clots by hemolysis with slight fibrinolysis, whereas clot erosion in AC was primarily due to hemolysis. HC achieved thrombolysis comparable to or better than AC, offering a safer, more targeted strategy, especially for disease due to RBC-rich clots such as non-cardioembolic stroke. The findings will advance mechanistic understanding of cavitation-induced clot degradation and support HC's clinical potential for thrombosis treatment.