<p>Ultrasound (US), as an efficient and non-invasive trigger, has been extensively explored in drug delivery and has many advantages, such as deep penetration, low invasiveness, and high biochemical precision. These advantages demonstrate the immense clinical potential of ultrasound. This study aimed to provide a comprehensive analysis of ultrasound-induced shear forces that exhibit covalent/non-covalent bond cleavage and reactive oxygen species (ROS)-mediated remote control of nanocarriers. By doing so, we can gain a deeper understanding of the vital role, significant advantages, and untapped potential of ultrasound in molecular-level drug activation. Furthermore, clinical translation faces challenges such as the low drug-loading capacity of polymer chains, frequency compatibility between ultrasound parameters and biological systems, insufficient ROS generation, and biocompatibility of current sonosensitizers. To solve these problems, ultrasound mechanochemistry has emerged as a versatile therapeutic modality to promote the development of medical treatments.</p>