The goal of the present study was to compare the drug release properties and stability of the nanoporous silica with different pore architectures as a matrix for improved delivery of poorly soluble drugs. For this purpose, three dimensional ordered macroporous (3DOM) silica with 3D continuous and interconnected macropores of different sizes (200 nm and 500 nm) and classic mesoporous silica (ie, Mobil Composition of Matter [MCM]-41 and Santa Barbara Amorphous [SBA]-15) with well-ordered two dimensional (2D) cylindrical mesopores were successfully fabricated and then loaded with the model drug indomethacin (IMC) via the solvent deposition method. Scanning electron microscopy (SEM), N2 adsorption, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were applied to systematically characterize all IMC-loaded nanoporous silica formulations, evidencing the successful inclusion of IMC into nanopores, the reduced crystallinity, and finally accelerated dissolution of IMC. It was worth mentioning that, in comparison to 2D mesoporous silica, 3DOM silica displayed a more rapid release profile, which may be ascribed to the 3D interconnected pore networks and the highly accessible surface areas. The results obtained from the stability test indicated that the amorphous state of IMC entrapped in the 2D mesoporous silica (SBA-15 and MCM-41) has a better physical stability than in that of 3DOM silica. Moreover, the dissolution rate and stability of IMC loaded in 3DOM silica was closely related to the pore size of macroporous silica. The colorimetric 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Cell Counting Kit (CCK)-8 assays in combination with direct morphology observations demonstrated the good biocompatibility of nanoporous silica, especially for 3DOM silica and SBA-15. The present work encourages further study of the drug release properties and stability of drug entrapped in different pore architecture of silica in order to realize their potential in oral drug delivery.