Efflux pump system-mediated bacterial multidrug resistance is one of the main causes of antibiotic failure. Therefore, it is necessary to develop a novel nanocarrier that could effectively inhibit drug-resistant bacteria by increasing the intake and retention time of antibiotics. Herein, we constructed a pH-responsive nanocarrier (MSN@FA@CaP@FA) with double folic acid (FA) and calcium phosphate (CaP) covered on the surface of mesoporous silica (MSN) by electrostatic attraction and biomineralization, respectively. Afterward, loading the nanocomposites with ampicillin (Amp) effectively increased the uptake and reduced the efflux effect in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by the specific targeting of FA. Moreover, Amp-MSN@FA@CaP@FA could specifically transport Amp to the bacterial infection site. Similarly, antibacterial experiments revealed that the Amp-MSN@FA@CaP@FA could significantly enhance the activity of Amp for inhibiting drug-resistant bacteria, without producing drug resistance. Additionally, the Amp-MSN@FA@CaP@FA could reduce the content of protein and inhibit the protein activity in drug-resistant bacteria, so that it destroyed the bacterial membrane and led to the bacteria death. In vivo antibacterial experiments showed that the Amp-MSN@FA@CaP@FA could effectively reduce the mortality of drug-resistant E. coli infection and promote wound healing of drug-resistant S. aureus infection. In summary, Amp-MSN@FA@CaP@FA has a potential for application in sustained-release nanostructures and to inhibit drug-resistant bacteria.