The production of wear debris particulate remains a concern due to its association with implant failure through complex biologic interactions. In the setting of unicompartmental knee arthroplasty (UKA), damage and wear of the components may introduce debris particulate into the adjacent, otherwise, healthy compartment. The purpose of this study was to investigate the in vitro effect of polymeric and metallic wear debris particles on cell proliferation, extracellular matrix regulation, and phagocytosis index of normal human articular chondrocytes (nHACs). In culture, nHACs were exposed to both cobalt-chromium-molybdenum (CoCrMo) and polymethyl-methacrylate (PMMA) wear debris particulate for 3 and 10 days. At 3 days, no significant difference in cell proliferation was found between control cells and cells exposed to both CoCrMo or PMMA particles. However, cell proliferation was significantly decreased for CoCrMo exposed nHACs at both 6 (P < 0.001) and 10 days (P < 0.001) and PMMA at 10 days (P < 0.001). Target gene expression displayed both a time- and material-dependent response to CoCrMo and PMMA particles. Significant differences in COL10A1, ACAN, VCAN, IL-1β, TNF-α, MMP3, ADAMTS1, CASP3, and CASP9 regulation were found between CoCrMo and PMMA exposed nHACs at day 3 with gene regulation returning to near baseline at 10 days. Results from our study indicate a role of wear debris induced cartilage degeneration after exposure to polymeric and metallic wear debris particulate, suggesting an additional pathway of cartilage breakdown, potentially manifesting in traditional clinical symptoms.