Otitis media, mainly caused by bacteria, is prevalent in young children and can cause hearing loss and growth retardation. Antibiotics are the most widely utilized treatment for otitis media, however, they can cause drug resistance and harmful side effects. In this study, we reported an antibacterial nanocomposite in combination with sonodynamic therapy that consists of herbal antibacterial agents such as Curcumin (CUR) and Tanshinone IIA (TSIIA), as well as Chitosan (CS), for the treatment of acute otitis media. CUR/TSIIA/CS nanocomposite (NC) with ultrasonic irradiation demonstrated that it could eliminate Staphylococcus aureus. In vivo experiments revealed that NC-mediated sonodynamic therapy had excellent antibacterial and anti-inflammatory activity, displaying a consistent performance comparable to ofloxacin. The therapeutic efficiency was attributed to capturing bacteria through spider-web-like effect and destroying bacteria through the reactive oxygen species generated under ultrasonic irradiation. Significantly, NC did not induce bacterial resistance and showed good biocompatibility. This study provides a novel strategy to develop an ultrasound-assisted nanocomposite with an enhanced antibacterial effect. Further, it unlocks new doors for the substitute of antibiotics to combat otitis media by establishing efficient therapeutic systems.Copyright © 2022 Elsevier B.V. All rights reserved.