Sonodynamic therapy and nanozyme have emerged as innovative technologies for anti-tumor therapy. Herein, we proposed a novel strategy to combination of piezoelectric-enhanced sonodynamic efficacy and enzyme-like activities for treatment of tumors. A piezoelectric material with enzyme-like activities of bismuth/cerium (Bi/Ce) co-doped sodium niobate (BCNO) was constructed. The co-doping of Bi/Ce ions in BCNO not only induced lattice distortion and bandgap reduction that remarkably enhanced piezoelectricity, but also endowed it with enzyme-like activities due to the change in valence state of Ce ions. Under irradiation of ultrasound (US), the piezoelectric effect of BCNO not only markedly amplified sonodynamic efficiency, but also facilitated the cascade reactions of glutathione peroxidase (GPx)/peroxidase (POD) and catalase (CAT)/glucose oxidase (GOx)/POD enzyme-like activities, which produced massive reactive oxygen species (ROS) for synergistic eradicating tumor cells and destructing tumors. The results demonstrated that the piezoelectric effect of BCNO caused severe oxidative stress, promoted glutathione depletion, induced ferroptosis, and interrupted the energy metabolism of tumor cells, ultimately achieving significant anti-tumor effects. This study developed a novel piezoelectric biomaterial with enzyme-like activities through a dual-ion doping strategy and provided a new solution for tumor therapy.