Complications from thrombosis constitute a massive global burden for human health. Current treatment methods have limitations and can cause serious adverse effects. Hydrodynamic cavitation (HC) is a physical phenomenon where bubbles develop and collapse rapidly within a moving liquid due to sudden pressure changes. These collapsing bubbles provide high targeted energy which can be used in a controlled environment with the help of microfluidic devices. This study introduces a new clot-on-a-chip (CoC) platform based on HC, evaluated for thrombolysis efficacy. The microfluidic device, paired with a polydimethylsiloxane (PDMS) microchip, generates cavitation bubbles at low upstream pressures (≤482 kPa), enabling microscale blood clot erosion. Different HC exposure conditions (varying pressure and duration) are assessed by changes in clot mass, diameter, and scanning electron microscopy (SEM). The largest mass reduction occurs at 482 kPa for 120 s, with a decrease of 6.1 ± 0.12 mg, while the most erosion in diameter of blood clots is obtained 482 kPa for 120 s with complete removal. SEM results show increasing damage to clot structure from less to more intense HC exposures. The CoC platform, at controlled pressures and durations, efficiently disrupts clot structure and offers a promising drug-free alternative for thrombolysis treatment.