Due to its modular and flexible design options, mesoporous silica provides ample opportunities when developing new strategies for combinatory antibacterial treatments. In this study, antibacterial ceria (CeO2) nanoparticles (NP) were used as core material, and were further coated with a mesoporous silica shell (mSiO2) to obtain a core@shell structured nanocomposite (CeO2@mSiO2). The porous silica shell was utilized as drug reservoir, whereby CeO2@mSiO2 was loaded with the antimicrobial agent capsaicin (CeO2@mSiO2/Cap). CeO2@mSiO2/Cap was further surface-coated with the natural antimicrobial polymer chitosan by employing physical adsorption. The obtained nanocomposite, CeO2@mSiO2/Cap@Chit, denoted NAB, which stands for “nanoantibiotic”, provided a combinatory antibacterial mode of action. The antibacterial effect of NAB on the Gram-negative bacteria Escherichia coli was proven to be significant in vitro. In addition, in vivo evaluations revealed NAB to inhibit the bacterial growth in the intestine of bacteria-fed Drosophila melanogaster larvae, and decreased the required dose of capsaicin needed to eliminate bacteria. As our constructed CeO2@mSiO2 did not show toxicity to mammalian cells, it holds promise for the development of next-generation nanoantibiotics of non-toxic nature with flexible design options.