Bacterial infections are a serious public health issue that threatens the lives of patients because of their ability to induce other lethal complications without prompt treatment. Conventional antibiotic therapy can cause bacterial resistance and other adverse effects. It is highly desirable to develop effective and antibiotic-independent therapeutic strategies to treat various kinds of bacterial infections. Herein, sonodynamic-enhanced piezoelectric materials MoS and CuOheterostructure that responds to exogenous ultrasound (US) and generates reactive oxygen for elimination are developed. It is shown in the results that the polariton charge induced by piezoelectric MoS nanosheets under US irradiation can accelerate the transfer of electric in CuO. Furthermore, US irradiation induces valence conversion from Cu(I) to Cu(II), which can accelerate glutathione oxidation significantly and destroy the bacterial antioxidant defense system. Hence, the as-prepared piezoelectric-enhanced sonosensitizer possesses a highly effective antibacterial efficacy of 99.85% against under US irradiation for 20 min, with good biocompatibility. Herein, effective ultrasonic piezocatalytic therapy is offered through constructing heterogeneous interfaces with ultrasonic piezoelectric response.