AbstractUsing piezoelectric bionanomaterials to promote the generation of reactive oxygen species (ROS) is being increasingly recognized in ultrasound (US)‐triggered tumor treatments. The mechanism underlying this innovative treatment involves US irradiation, which activates the built‐in electric field (BIEF) and induces energy‐band bending in piezoelectric materials (PEMs). In this study, Sr0.5Ba0.5Nb2O6 (SBN) nanorods (NRs) are synthesized using a molten salt method. Subsequently, oxygen‐vacancy (OV)‐rich SBN/Sr2Nb2O7 (SBN/SNO) heterojunction nanocomposites (NCs) are fabricated via H2 annealing of the SBN NRs. The engineering strategy focused on enhancing ROS generation, thereby augmenting the piezoelectric catalytic activity of the NCs. This configuration ensures that the BIEF and heterojunction‐induced field act synergistically to provide a sustained driving force for the separation of electron‐hole (e−‐h+) pairs. Importantly, the OVs on the surfaces of the H2‐annealed SBN NRs create electron‐rich sites, which substantially enhance their piezocatalytic capabilities. In vitro and in vivo analyses of hepatocellular carcinoma (HCC) models demonstrate the significant cytotoxic and tumor‐inhibitory capabilities of this rich OV‐mediated sonopiezoelectric therapy (SPT) and illustrate its potential as a promising therapeutic approach against cancer.