Ultra-high molecular weight polyethylene (UHMWPE) is the most widely used biopolymer for articulating surfaces, such as an acetabular cup liner interfacing with a metal/ceramic femoral head. However, the formation of wear debris leads to the aseptic loosening of implants. Thus, in order to improve the life span via enhancing the fretting wear resistance, UHMWPE is reinforced with ZnO/Ag nanoparticles. It is envisaged that the ZnO/Ag addition will also exhibit antibacterial properties. In the current study, the synergetic effect of the reinforcement of ZnO/Ag nanoparticles (0–3 wt.% combinations) on the fretting wear behavior of a UHMWPE matrix is assessed. The phase characterization of compression- molded UHMWPE-Ag-ZnO biopolymer nanocomposites has elicited the retention of starting phases. All samples were processed at >98% density using compression molding. Silver and ZnO reinforcement showed enhanced hardness ~20.4% for U3A and 42.0% for U3Z. Fretting wear performance was evaluated at varying loads (5–15 N), keeping in mind the weight at different joints, with constant frequency (5 Hz) as well as amplitude of oscillation (100 µm). Laser surface profilometry showed change of wear volume from 8.6 × 10−5 mm3 for neat polymer to 5.8 × 10−5 mm3 with 1 wt.% Ag + 1 wt.% ZnO reinforcement (at 15 N load). Consequently, the mechanics of resistance offered by Ag and ZnO is delineated in the UHMWPE matrix. Further, S. aureus viability reduction is ~28.7% in cases with 1 wt.% Ag addition, ~42.5% with 1 wt.% ZnO addition, but synergistically increase to ~58.6% and 47.1% when each of Ag and ZnO is added with 1 wt.% and 3 wt.%, respectively (when compared to that of the UHMWPE control sample). Increased wear resistance and superior bioactivity and enhanced anti-bacterial properties of 1 wt.% Ag + 1 wt.% ZnO and 3 wt.% Ag + 3 wt.% ZnO shows the potential use of ZnO-Ag-UHMWPE biopolymer composites as an articulating surface.