Surface modification of inert biomaterials is an alternative to provide bioactivity, thus improving cellular response and tissue-implant integration. Different techniques aim to change the physicochemical properties of surfaces, including coatings, chemical functionalization, and plasma, among others. This work presents a series of modifications of the zirconia ceramic surface, a material used in orthopedic and dentistry, and of the Polyether ether ketone (PEEK) polymeric surface, used in orthopedic, craniofacial, and spine reconstruction surgery. Firstly, the plasma treatment activated the surfaces of the materials and increased their wettability and adhesión properties. Then, they were coated and functionalized with different biomolecules. The cellular response of the CaCo2 epithelial cells and NIH/3T3 fibroblasts was analyzed regarding adhesion, spreading, and proliferation. The results indicated an increase in cellular activity to a greater or lesser extent depending on the type of modification.