High intensity focused ultrasound (HIFU), as one of the most advanced and preferred cancer treatment modes, has shown great promise due to its minimal invasiveness and irradiation-free nature. However, a key limiting factor for its further clinical application is its relatively low therapeutic potency. In this study, CaO2@SiO2 NPs were developed for efficient O2 bubble-assisted HIFU surgery against tumors. After entering the tumor sites, these nanoparticles can release O2 and H2O2, achieving enhancement of US imaging signals and improved potency of HIFU surgery. In addition, local temperature increase during HIFU treatment could trigger O2 generation by the conversion of unstable H2O2 into O2 gas, further augmenting the efficacy of HIFU treatment. This work not only provides a paradigm of CaO2 for cancer management in nanomedicine, but also presents an efficient way for bubble-enhanced HIFU surgery.