Well-defined nanocomposite structures have received significant attention due to their superior combinatorial properties. Rational tuning of the core and shell of the nanostructure(s) can offer potent antibacterial activity. Such advanced core-shell nanocomposite methodologies allow not only the incorporation of antibacterial agents on the shell but also provide its stability and nurture antibacterial activity. Herein, antibiotic zinc oxide-curcumin (ZnO-Cum) core-shell nanoparticles for antibacterial application were synthesised. The ZnO-Cum core-shell nanoparticles were prepared by curcumin nanolayer deposition on zinc oxide nanoparticles via a sonication process. The resulting ZnO-Cum core-shell nanoparticles were spiracle in shape with a ∼45 nm ZnO core and ∼12 nm curcumin shell layer size, respectively, determined by transmission electron microscopy. X-ray diffraction analysis confirmed the formation of a core-shell crystal structure. Additionally, UV-DRS and ATR-FTIR spectral analysis support the existence of ZnO and curcumin in a core-shell nanocomposite. The antibacterial activities of nanoparticles developed were studied against Staphylococcus aureus and Streptococcus pneumoniae and Escherichia coli and Shigella dysenteriae bacterial stains using the diffusion method. A greater inhibition of the growth of Gram positive and negative bacteria was noticed upon treatment with core-shell ZnO and curcumin nanoparticles than the commercial antibiotic amoxicillin which indicates their antibacterial property. The findings of this study provide evidence that the zinc oxide-curcumin core-shell nanoparticles may be highly promising for antibacterial and biomedical applications.