Poly-ether-ether-ketone (PEEK) is a polymeric material that is often used in biomedical applications due to its excellent mechanical properties and radiolucency; this material is, in general, biologically inert. In recent decades, thermally sprayed biocompatible coatings have been widely employed in metallic implants to improve the osseointegration process in the human body. Thus, not surprisingly, thermally sprayed biocompatible coatings can be envisaged as an excellent alternative to improve the material's surface properties. However, there is little information in the literature about the deposition of thermally sprayed bioactive coatings on polymeric substrates. In the present study, a titanium dioxide (TiO2) powder was plasma-sprayed on PEEK substrates acting as a bond coat to further deposition of hydroxyapatite (HA)/bioactive glass multilayered coatings. The design of experiments methodology was employed to produce coatings with tailored properties. A key aspect in this work is how the experiments were carried out to understand the effect of powder features, such as chemical composition, on the deposition of the ceramic coatings on the PEEK substrate. Heating/cooling physical laws were employed to discuss the results obtained. The methodology employed in this work allowed to deposit a multilayered coating with adhesion strength of about 50 MPa on PEEK substrates measured using scratch test. The coatings' structural, morphological, chemical, thermal, and mechanical evaluation was performed using X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, differential scanning calorimetry, and micro indentation test, respectively. In-vitro tests were also performed on these coatings under static simulated conditions. The results show that the PEEK's surface can be successfully functionalized, turning it from showing an inert behavior to displaying bioactivity by applying a HA-based bilayer or multilayered coating.