Tissue engineering (TE) and nanomedicine require devices with hydrophilic surfaces to better interact with the biological environment. This work presents a study on the wettability of cubic silicon-carbide-based (SiC) surfaces. We developed four cubic silicon-carbide-based epitaxial layers and three nanowire (NW) substrates. Sample morphologies were analyzed, and their wettabilities were quantified before and after a hydrogen plasma treatment to remove impurities due to growth residues and enhance hydrophilicity. Moreover, sample biocompatibility has been assessed with regard to L929 cells. Our results showed that core–shell nanowires (SiO2/SiC NWs), with and without hydrogen plasma treatment, are the most suitable candidate material for biological applications due to their high wettability that is not influenced by specific treatments. Biological tests underlined the non-toxicity of the developed biomaterials with regard to murine fibroblasts, and the proliferation assay highlighted the efficacy of all the surfaces with regard to murine osteoblasts. In conclusion, SiO2/SiC NWs offer a suitable substrate to develop platforms and membranes useful for biomedical applications in tissue engineering due to their peculiar characteristics.