Abstract Piezoelectric catalysis for tumor treatment is an emerging method for generating reactive oxygen species (ROS). However, the development and optimization of piezoelectric catalytic nanomaterials remain the major challenge. Herein, by regulating the internal and surface defects of graphene phase carbon nitride (defect‐engineered g‐C 3 N 4 ), its piezoelectricity and sonocatalytic performance is enhanced, thus achieving efficient tumor treatment. By reducing bulk defects, the charges excited by ultrasound (US) within the defect‐engineered g‐C 3 N 4 can migrate more rapidly to the material surface, thereby enhancing their participation in redox reactions. Increasing surface defects not only introduce more active sites on the surface of defect‐engineered g‐C 3 N 4 but also enhance the asymmetry of the defect‐engineered g‐C 3 N 4 structure, resulting in excellent piezoelectric properties. This defect‐engineered g‐C 3 N 4 nanosheet can effectively generate ROS in tumor cells and induce tumor cell apoptosis under US stimulation. This work not only introduces a method to enhance the piezoelectric catalytic performance of g‐C 3 N 4 but also expands the potential application of defect‐engineered piezoelectric materials to tumor treatment.