Bioactive glasses are widely studied as biomaterials for bone contact applications. In this research work, the opportunity to modify the surface of a bioactive glass with polyphenols (gallic acid, and natural polyphenols extracted from red grape skin and green tea leaves) has been investigated in order to induce a selective anti-tumor activity in vitro. The presence of surface grafted molecules has been optically proved by fluorescence microscopy exploiting their auto-fluorescence. Direct and indirect cytotoxicity assays have been performed with human bone osteosarcoma cells (U2OS) and human fetal pre-osteoblasts (hFOB), as well as the quantification of oxygen and nitrogen reactive species (RONS) engendered from cells in response to the materials. Finally, the DNA damage of U2OS cells upon contact with the bioactive glass has been evaluated in order to verify any selective cytotoxic activity of functionalized materials against cancer cells. Results showed a selective cytotoxic activity of functionalized bioactive glasses toward osteosarcoma cells that was particularly evident when cells were cultivated directly onto glasses surface. Moreover, the presence of grafted polyphenols increased the RONS production and induced a permanent DNA damage on the U2SOS cells while they promote a certain anti-inflammatory action toward hFOB. These preliminary results suggest polyphenols grafted bioactive glasses as promising material for bone substitution in cancer treatment.