Among various novel antimicrobial therapies, sonodynamic therapy (SDT) exhibits its advantages for the treatment of bacterial infections due to its high penetration depth and low side effects. In this study, a new nanosonosensitizer (HFH@ZIF-8) that loads sonosensitizer hematoporphyrin monomethyl ether (HMME) into zeolitic imidazolate framework-8 (ZIF-8), was constructed for killing multidrug-resistant (MDR) bacteria and treatment of in vivo infection diseases by SDT. In particular, the developed HFH@ZIF-8 exhibited enhanced water-solubility, good biocompatibility, and improved disease-targeting capability for delivering and releasing HMME and ablating the infected lesion. More importantly, the presence of oxygen-carrying hemoglobin for HFH@ZIF-8 can offer sufficient oxygen consumption by SDT, augmenting the efficacy of SDT by improving ROS generating efficiency against deep tissue multidrug-resistant bacterial infection. Therefore, this study paves a new avenue for treating infection disease, particularly for antibiotic resistant bacterial infection.