Novel poly(ether ether ketone) (PEEK) based nanocomposites have been fabricated via melt-blending by addition of a carboxylated polymer derivative covalently grafted onto the surface of hydroxyl-terminated ZnO nanoparticles. Their morphology, thermal, mechanical, tribological, and antibacterial properties have been analyzed and compared with those of composites reinforced with pristine ZnO. The Fourier transform infrared (FT-IR) spectra corroborate the success of the grafting reaction, showing the appearance of signals related to ester linkages. Microscopic observations demonstrate that the polymer grafting improves the nanoparticle dispersion within the matrix. A progressive rise in thermal stability and flame retardant ability is found with increasing ZnO concentration, with an exceptional increment in the maximum degradation rate temperature of 70 °C at 5.0 wt % loading. The crystallization and melting temperature of PEEK decrease upon incorporation of the grafted nanofillers, attributed to the restrictions on polymer chain mobility and crystal growth imposed by the strong ZnO-matrix interactions. Nanocomposites with polymer-grafted nanoparticles exhibit higher stiffness, strength, ductility, toughness and glass transition temperature whilst lower coefficient of friction and wear rate than the neat polymer and composites with bare ZnO. Further, they show superior antibacterial activity against both the Gram-negative Escherichia coli and the Gram-positive Staphylococcus aureus bacteria. The antimicrobial effect increases upon raising nanoparticle content, and is stronger on E. coli. The approach used in this work is a simple, scalable, and efficient method to improve the performance of PEEK/ZnO nanocomposites for use in biomedical applications such as trauma, orthopedics, and spinal implants.