In recent years, the application of hollow mesoporous silicon nanoparticles in the biomedical field has attracted much attention because of their excellent features. In this study, the sonosensitizer curcumin (Cur), the chemotherapy drug doxorubicin (Dox), and the perfluoropropane (C 3 F 8 ) gas were loaded into a multifunctional hollow mesoporous silica nanoparticle (MHMSN). The surface of MHMSN was modified with a biotin molecule and acid-sensitive groups (cis-aconitic anhydridepolyethylene glycol, CDM-PEG). The as-prepared multifunctional nanoparticle (CDF-MHMSN) demonstrates improved therapeutic efficacy and enhanced tumor contrast ultrasound performance. Surface-modified CDM-PEG can improve the blood circulation ability of nanoparticles and peel off in the acidic tumor microenvironment, which can enhance the endocytosis of cancer cells. As a sonosensitizer, Cur could generate reactive oxygen species (ROS) under ultrasound stimulation to kill tumor cells and reduce the multidrug resistance of tumor cells to the Dox by inhibiting the expression of P-glycoprotein. Overall, CDF-MHMSN exhibits good biocompatibility, excellent ultrasound imaging capability, and effective antitumor ability, which may contribute to improving the treatment strategy for hepatocellular carcinoma.