The melting behavior of nanostructured organic materials (drugs) embedded into a cross-linked polymeric matrix was studied for the first time. The complex microstructure of these nanocomposites, yielded by the polymer matrix in which molecular clusters and nanocrystals of drug plus a cospiquous fraction of water are confined, demanded synergic application of thermal analysis and temperature resolved X-ray diffraction. A relevant depression of the melting point of the embedded drug with respect to the bulk drug was experimentally demonstrated. The coherent domain size of the embedded drug nanocrystals was independently evaluated by thermal and diffraction data and results were in agreement. This indicates that the adopted thermodynamic melting model, based on Laplace and Gibbs-Duhem equations and developed for simpler systems, can be successfully assessed for describing drug/polymer nanocomposites, and, potentially, other classes of organic nanocomposites.