The sensitization performance of sonosensitizers plays a key role in the sonodynamic therapy (SDT) effect. Herein, ZnSnO:Nd nanoparticles with R3c phase/amorphous heterogeneous structure are developed by phase engineering strategy and applied as an ideal sonosensitizer. In the crystalline perovskite-type ZnSnO:Nd, the substitution of the Zn with Nd causes the O 2p non-bonded state to move toward the Fermi level, which optimizes the band structure for ultrasound sensitization by reducing bandgap. Meanwhile, the unequal charge substitution can also form electron traps and oxygen vacancies to shorten the electron migration distance, which accelerates the electron–hole separation and inhibits carrier recombination, thus improving the acoustic sensitivity. Moreover, the dangling bonds exposed on the surface of amorphous ZnSnO:Nd provide more active sites, and the localized states of the amorphous phase may also promote carrier separation, resulting in synergistic SDT effect. In particular, the Zn released from ZnSnO:Nd in the acidic tumor microenvironment (TME) reduces the adenosine triphosphate production by inhibiting the electron transport chain, which promotes the tumor cell apoptosis through destroying the redox balance of TME. Combining the inherent second near infrared and computed tomography imaging capabilities, this ZnSnO:Nd nanoplatform shows a promising perspective in clinic SDT field.