With the development of nanomedicine, utilization of nanomaterials to catalyze the generation of excess reactive oxygen species (ROS) under exogenous ultrasound stimulation has attracted widespread attention for disease therapy, which is called sonodynamic therapy (SDT). Currently, development of high-efficiency sonosensitizers that can be used in SDT to improve ROS yield remains one of the most important challenges for current research and future clinical translation. Recently, benefited from the development of piezotronics and piezophototronics, novel sonosensitizers based on piezoelectric semiconductor nanomaterials have shown promising applications in SDT. In this review, we outline the structures and properties of piezoelectric semiconductors, and introduce the presumed mechanism of SDT with piezoelectric semiconductors. The newest research progresses on using piezoelectric semiconductor as sonosensitizer in cancer treatments and antibacterial applications are summarized. Finally, the existing challenges and future development trends in this field are proposed.