Sonodynamic therapy (SDT) as a non-invasive antitumor strategy has been widely concerned. However, the rapid electron (e) and hole (h) recombination of traditional inorganic semiconductor sonosensitizers under ultrasonic (US) stimulation greatly limits the production of reactive oxygen species (ROS). Herein, we report a unique Zn/Pt dual-site single-atom driven difunctional superimposition-augmented TiO-based sonosensitizer (Zn/Pt SATs). Initially, we verify through theoretical calculation that the strongly coupled Zn and Pt atoms can assist electron excitation at the atomic level by increasing electron conductivity and excitation efficiency under US, respectively, thus effectively improving the yield of ROS. Additionally, Zn/Pt SATs can significantly enhance ferroptosis by producing more ROS and sonoexcited holes under US stimuli. Therefore, the establishment of dual-site single-atom system represents an innovative strategy to enhance SDT in cancer model of female mice and provides a typical example for the development of inorganic sonosensitizer in the field of antitumor therapy.