AbstractSonodynamic therapy (SDT) has been widely reported as a noninvasive and high‐penetration therapy for cancer; however, the design of an efficient sonosensitizer remains an urgent need. To address this issue, molybdenum disulfide nanoflowers (MoS2 NF) as piezo‐sonosensitizers and introduced sulfur vacancies on the MoS2 NF (Sv‐MoS2 NF) to improve their piezoelectric property for cancer therapy are designed. Under ultrasonic mechanical stress, the Sv‐MoS2 NF resulted in piezoelectric polarization and band tilting, which enhanced the charge carrier separation and migration. This resulted in an improved catalytic reaction for reactive oxygen species (ROS) production, ultimately enhancing the SDT performance. Thanks to the high efficiency of ROS generation, the Sv‐MoS2 NF have demonstrated a good anticancer effect in vitro and in vivo. Following a systematic evaluation, Sv‐MoS2 NF also demonstrated good biocompatibility. This novel piezo‐sonosensitizer and vacancy engineering strategy provides a promising new approach for achieving efficient SDT.