Antibacterial nano-platforms have been established in response to the growing incidence of bacterial resistance to traditional antibiotics guaranteeing an appealing approach to tackle this resistance. The objective of this research is to improve vancomycin's antibacterial activity as a potent nano-platform against a variety of resistant bacteria. Cerium oxide nanoparticles (CeO2NPs) and cerium oxide nanoparticles functionalized with vancomycin (CeO2-VanNPs) were synthesized using the hydroxide-mediated method. Both CeO2NPs and CeO2-VanNPs were properly synthesized and exhibited particle sizes of 2.5 ± 0.23 and 5 ± 0.4 nm, along with hydrodynamic size of 31.01 ±2.4 and 151.5 ±3.2 nm, respectively. The zeta potentials for CeO2NPs and CeO2-VanNPs were measured to show +28.8 and +10.7 mV, respectively indicating the stability of the synthesized nanoparticles. The in-vitro antibacterial activity of vancomycin, CeO2-NPs and CeO2-VanNPs against clinically isolated gram-negative (Escherichia coli) and gram-positive (Staphylococcus aureus) bacteria was investigated. The combination of CeO2-NPs and vancomycin in a single nanostructure showed a synergistic effect in inhibiting bacterial growth, where Staphylococcus aureus and E. coli displayed larger inhibition zones of 39 ±21 mm and 29 ±24 mm, respectively as compared to vancomycin only. This enhanced antibacterial activity indicates the potential of CeO2-VanNPs as promising alternative antibiotics for combating vancomycin-resistant bacteria.