The development of novel sonosensitizers with outstanding reactive oxygen (ROS) generation capacity and great biocompatibility poses a significant challenge for the clinical practice of sonodynamic therapy (SDT). In this work, hemoglobin (Hb) with natural metalloporphyrin was first shown to possess great potential as a sonosensitizer. Compared with traditional organic sonosensitizers, Hb had satisfactory sono-sensitizing efficiency because four the porphyrin molecules were separated by four polypeptide chains. This effectively avoided the problem of low ROS quantum yield caused by the stacking of hydrophobic porphyrins. Meanwhile, Hb is an efficient and safe oxygen carrier that may release O at hypoxic tumors site, which improved tumor oxygenation and subsequently enhanced SDT efficacy. Therefore, Hb was integrated with zeolitic imidazolate framework 8 (ZIF-8) to form a nanoplatform that demonstrated a potent suppression effect on deep-seated tumors under ultrasound irradiation.