We describe here favorable modulation of osteoblasts functions and cell–substrate interactions in hybrid silicone elastomers consisting of biocompatible graphene oxide. Pressure induced curing was used to synthesize the hybrid silicone elastomer with high strength–high elongation combination. It was intriguing that the cell–substrate interactions in the hybrid silicone elastomer were observed to be significantly different from those observed in stand alone silicone. The origin of differences in cell–substrate interactions in terms of cell attachment, viability, and proliferation and assessment of proteins actin, vinculin, and fibronectin are addressed and attributed to physico-chemical properties (topography and hydrophilicity) and to the presence of graphene oxide. The end outcome of the study is a new family of nanostructured polymer composite with desired (enhanced cell functions) and bulk properties (long term stability—high strength-at-break). The integration of cellular and molecular biology with material science and engineering described here provides an insight into the ability to modulate cellular and molecular reactions in promoting osteoinductive signaling of surface adherent cells, in the present case, osteoblasts for joint reconstruction.