Graphene oxide (GO) is av ersatile platform with unique properties that have found broad applications in the biomedical field. Double functionalization is ak ey aspecti n the designo fmultifunctional GO with combined imaging, targeting, and therapeutic properties. Compared to noncovalent functionalization, covalents trategies lead to GO conjugates with ah igher stability in biological fluids. However, only af ew double covalentf unctionalization approaches have been developed so far.T he complexity of GO makes the derivatization of the oxygenated groups difficult to control. The combination of an ucleophilic epoxide ring opening with the derivatization of the hydroxyl groups through esterification or Williamson reaction was investigated. The conditions were selective and mild, thus preserving the structure of GO. Our strategy of double functionalization holds great potentialf or different applications in which the derivatization of GO with different molecules is needed, especiallyi nt he biomedical field.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.Scheme1.Double-functionalization approach combining the opening of the epoxides and the Williamson reaction (each reaction is showno nly on one functional group for clarity).Scheme2.Double functionalization of GO performedbyc ombining the epoxide opening with esterification on GO-A (each reaction is shownonly on one functional groupf or clarity).