Poly (methyl methacrylate) (PMMA) is an extensively used implant material in biomedical devices. Biofilm formation creates issues in PMMA-based biomedical implants, while emergence of drug resistant pathogens poses an additional complication. Hence development of surfaces that resist bacterial colonisation is extremely desirable. In this context, nanomaterials are among the potential choices. In the present work, nanocomposites (NCs) were developed by incorporation of chemically synthesized nanoparticles of CuO, cetyl trimethyl ammonium bromide (CTAB) capped CuO and ZnO (singly and in combination) in PMMA. The efficacy of these NCs was assessed against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) bacteria which are prevalent in many implant-associated infections. Results revealed species-specific response of the bacteria towards nanomaterials. CuO NC (0.1% (w/v)) was more effective against E. coli, while CTAB capped CuO NC and ZnO NC were very effective against S. aureus. Furthermore, combination of nanoparticles improved efficacy of nanocomposites against both the bacterial species. In vitro cytotoxicity assay using L6 myoblast cell line showed that all NCs at 0.1% (w/v) were biocompatible, showing >85% cell viability. The present study suggests that combination of NPs is a promising option to combat implant infection by multiple organisms. © 2019