We report the preparation of a hybrid chitosan/silica three-dimensional (3D) scaffold loaded simultaneously with two model hydrophilic substances, ibuprofen sodium salt and erioglaucine disodium salt. The first substance is entrapped in situ during the preparation of chitosan submillimetric beads by ionotropic gelation with sodium triphosphate, while the latter is post-loaded during the scaffold formation. Controlled release experiments carried out under neutral conditions demonstrate that the presence of nanostructured silica within the polymer matrix retards the release of both hydrophilic substances and increases the structure stability of the scaffold. Release profiles can be fitted to a two-component model with a diffusion-controlled term (Korsmeyer-Peppas model), which dominates the release of the post-loaded substance, and a second swelling/erosion term, which becomes relevant for the in situ entrapped drug.