Nanocomposites of biocompatible polyphenylsulfone (PPSU) and titanium dioxide (TiO2) nanoparticles have been prepared via ultrasonication and solution casting. Their structure, surface morphology, water uptake, thermal, mechanical, tribological and antibacterial properties have been investigated in detail. FT-IR analysis revealed the existence of strong hydrogen bonding interactions between the sulfone group of PPSU and the hydroxyl moieties of the nanoparticles, which were homogenously dispersed within the matrix without adding coupling agents. The incorporation of TiO2 reduced the water absorption and increased the thermal stability of the polymer under both inert and oxidative conditions. Furthermore, the nanocomposites exhibited greatly enhanced mechanical performance (storage and Young's moduli, tensile strength and toughness, glass transition and heat distortion temperature) compared to neat PPSU, confirming the formation of a strong nanofiller-matrix interface necessary for an efficient load transfer. Moreover, their tensile properties were retained after exposure to several cycles of steam sterilization or to simulated body fluid (SBF) at physiological temperature. Outstanding improvements in the tribological performance under both dry and SBF conditions were also attained, demonstrating the suitability of these nanoparticles for providing wear resistance to the matrix. The nanocomposites exhibited inhibition against both Gram-positive and Gram-negative bacteria with and without UV illumination, which was progressively enhanced with increasing TiO2 loading. These biomaterials are very promising for use in biomedical applications like orthopaedic and trauma implants.