The structural properties of the mesoscopically confined drug and drug–drug and drug–matrix interactions were investigated in model drug-delivery systems prepared from nonfunctionalized and functionalized SBA-15 mesoporous silicate matrices, loaded with different amounts of indomethacin molecules. 1H MAS and 1H–13C CPMAS NMR spectroscopy indicated that only when the concentration of indomethacin within the mesopores becomes sufficiently high (when the mass fraction of indomethacin within the sample exceeds 0.15) do hydrogen bonds between the drug molecules become abundant. Nitrogen sorption analysis and comparison of 1H spin–lattice relaxation times in progressively loaded SBA-15 matrices suggested that at low loading concentrations indomethacin forms a layer on the silicate walls of the mesopores and that at moderate or high loading concentrations rigid nanoparticles that extend throughout the entire mesopore cross section are formed. 1H–29Si HETCOR NMR spectra indicated that the interaction between the indomethacin molecules and the silicate surface was moderate to weak. The 1H–13C CPMAS NMR spectrum of indomethacin embedded within the mesopores of SBA-15 closely resembled the spectrum of the bulk amorphous indomethacin and did not allow to draw firm conclusions about the molecular conformation and the packing of the drug molecules within the pores. On the contrary, variable-temperature 1H spin–lattice relaxation measurements showed that the mesoscopically confined indomethacin is significantly different from the bulk amorphous indomethacin. It does not become rubbery, and it exhibits a solid–solid transition at 363 K that is similar to the phase transition of the crystalline indomethacin solvate with tetrahydrofuran. When indomethacin is incorporated into the functionalized SBA-15 matrix, the interactions between the embedded drug molecules and the walls of the matrix are enhanced.