Ultrasound (US)‐mediated sonodynamic therapy (SDT) has the advantages of non‐invasiveness and deep tissue penetration. Nanosystems are prominently used in sonosensitization; however, most nano‐sonosensitizers have a low reactive oxygen species (ROS) yield, thus restraining the application of SDT. Sodium molybdenum bronze nanoparticles (SMB NPs) with rich oxygen vacancies are developed and interlayer gaps of molybdenum trioxide nanobelts are expanded. Owing to the increased oxygen vacancy density and wide interlayer gap‐induced narrower band gap of SMB NPs, the electrons (e–) and holes (h+) generated by US are separated more rapidly, and oxygen vacancies prevent electrons–holes recombination under US irradiation. SMB NPs exhibit a second near‐infrared (NIR‐II) photothermal effect to promote the generation of ROS by the sonosensitizer. The SMB NPs system is successfully realized to eliminate Staphylococcus aureus (S. aureus) and dissipate biofilm. Therefore, multimodal therapy using SMB NPs serves as an effective and promising regimen for deep‐seated bacterial infections. The newly developed Mo‐based sonosensitizer is presented for the first time to demonstrate excellent antimicrobial activity through hyperthermia‐promoting SDT therapeutics. This work proposes a novel strategy in the field of NIR‐II photo‐amplified SDT with Mo‐based materials for bacterial eradication and other important biomedical applications. The newly developed Mo‐based sonosensitizer is presented for the first time to demonstrate excellent eradicate bacteria in deep‐seated infected tissues in vivo through photothermal‐amplified sonodynamic therapy (SDT) to accelerate abscess healing, which can open a new window in the field of NIR‐II photo‐amplified SDT with Mo‐based materials for bacterial eradication and other biomedical applications.