AbstractSonodynamic therapy (SDT) has attracted widespread attention due to its non‐invasiveness and deep tissue penetration. However, the development of efficient sonodynamic nanoplatforms to improve the therapeutic efficiency is still one of the main challenges of current research. In this work, a new type of sonosensitizer prepared by a simple method, manganese carbonate nanoparticles (MnCO3NPs), is used for enhanced SDT. MnCO3NPs could generate large amounts of1O2and •OH under ultrasound irradiation. At the same time, CO2and Mn ions could be released in a weak acid environment due to the excellent degradability of MnCO3NPs. The CO2bubbles caused cell necrosis by ultrasonic cavitation and used for ultrasound imaging. And Mn ions activated the mitochondrial cell apoptosis pathway. In vivo experiments proved that this sonosensitizer with mitochondrial regulatory capacity showed high tumor inhibition rates for enhanced sonodynamic tumor therapy.