High-performance oxide ceramics (HPOC), such as alumina, zirconia, and dispersion ceramics thereof are successfully used as articulating components in joint arthroplasty. HPOC exhibit excellent wear resistance, high strength, and cytocompatible behavior; however, they lack sufficient tissue bonding capability. Thus, they are primarily deployed as low-wear-bearing articulating components in arthroplasty without direct tissue contact, although proper cellular stimulation would hold significant advantages. Here, we describe a surface modification approach for HPOC, enabling hydrolytically stable interfacial binding of c(RGDyK) peptides and BMP-2 proteins to significantly improve the adhesion and osteogenic differentiation of human mesenchymal stem cells (hMSCs) without altering the mechanical properties of the underlying ceramic substrates. Analyses of cellular attachment of murine fibroblasts (L929), human alveolar basal epithelial cells (A549), hMSCs on c(RGDyK), and osteogenic differentiation of hMSCs on BMP-2-coated interfaces demonstrate significant improvements of cell adhesion and an enhanced osteogenic differentiation potential in vitro. The presented approach provides a strategy for the development of a novel class of bioactive HPOC with osseointegration potential that could lead to novel therapeutic solutions for biomedical applications. Furthermore, the developed surface modification is designed in a way to be readily translated to other medically employed bioinert materials in the future.