Owing to its deep penetration capability, microwave (MW) therapy has emerged as a promising method to eradicate deep-seated acute bone infection diseases such as osteomyelitis. However, the MW thermal effect still needs to be enhanced to achieve rapid and efficient treatment of deep focal infected areas. In this work, the multi-interfacial core-shell structure barium sulfate/barium polytitanates@polypyrrole (BaSO/BaTiO@PPy) was prepared, which exhibited enhanced MW thermal response via the well-designed multi-interfacial structure. To be specific, BaSO/BaTiO@PPy achieved rapid temperature increases in a short period and efficient clearance of Staphylococcus aureus (S. aureus) infections under MW irradiation. After 15 min MW irradiation, the antibacterial efficacy of BaSO/BaTiO@PPy can reach up to 99.61 ± 0.22%. Their desirable thermal production capabilities originated from enhanced dielectric loss including multiple interfacial polarization and conductivity loss. Additionally, in vitro analysis illuminated that the underlying antimicrobial mechanism was attributed to the noticeable MW thermal effect and changes in energy metabolic pathways on bacterial membrane instigated by BaSO/BaTiO@PPy under MW irradiation. Considering remarkable antibacterial efficiency and acceptable biosafety, we envision that it has significant value in broadening the pool of desirable candidates to fight against S. aureus-infected osteomyelitis. STATEMENT OF SIGNIFICANCE: The treatment of deep bacterial infection remains challenging due to the ineffectiveness of antibiotic treatment and the susceptibility to bacterial resistance. Microwave (MW) thermal therapy (MTT) is a promising approach with remarkable penetration to centrally heat up the infected area. This study proposes to utilize the core-shell structure BaSO/BaTiO@PPy as an MW absorber to achieve localized heating under MW radiation for MTT. In vitro experiments demonstrated that the disrupted bacterial membrane is primarily due to the localized high temperature and interrupted electron transfer chain. As a consequence, its antibacterial rate is as high as 99.61% under MW irradiation. It is shown that the BaSO/BaTiO@PPy is a promising candidate for eliminating bacterial infection in deep-seated tissues.