High-intensity focused ultrasound (HIFU), with inherent advantages of improved ultrasonic depth and low off-target damage, holds the promising capability for glioma treatment, but the relatively long therapeutic time and potential physical complications may hamper its clinical application. Herein, a bovine serum albumin (BSA)-based nanoplatform with in situ growth of MnO₂ was synthesized, and Protoporphyrin IX (PpIX) was further anchored to obtain a versatile PpIX@MnO₂@BSA nanoplatform (denoted as BMP). By employing HIFU as the exogenous irradiation source, a high-efficacy sonodynamic therapy (SDT) is developed, in which the excited BMP enables the production of tumoricidal reactive oxygen species (ROS). The inherent tumor microenvironment (TME)-responsive property of MnO₂ endows BMP with specific T₁-weighted magnetic resonance imaging (MRI) by releasing Mn²⁺, and the simultaneously generated O₂ facilitates hypoxia alleviation as well as ¹O₂ generation. Compared with HIFU therapy alone, suppression of glioma growth and improved survival benefits are achieved through the designed TME-responsive nanocomposite under HIFU exposure. The high-efficacy SDT strategy combining BMP and HIFU demonstrated favorable TME-responsive T₁-weighted MRI, hypoxic environment alleviation, and anti-tumor capability, providing a perspective paradigm for MRI-guided glioma treatment.