Silica-sepiolite heterostructured materials have been prepared as novel nanoarchitectures by generation of SiO2 nanoparticles (NPs) on the surface of the sepiolite fibrous clay mineral. The synthetic approach implies the use of organo-sepiolites dispersed in isopropanol to which is incorporated a selected silicon alcoxysilane, such as tetramethoxysilane (TMOS), that then is slowly hydrolyzed to procure the formation of a viscous gel under ultrasound irradiation. Once the sol-gel reaction is achieved the intermediate silica-sepiolite organo-heterostructures can be submitted to a thermal treatment for the removal of the organic matter, which finally gives rise to the silica-sepiolite nanoarchitectures. Influence of different experimental variables, such as nature of both alkoxysilane precursor and organo-sepiolite as well as their relative ratio in the reaction media, in the characteristics of both intermediate silica-sepiolite organo-heterostructures and final nanoarchitectures has been explored. Both type of heterostructured materials have been characterized by means of diverse experimental techniques such as CHN chemical analysis, TG-DTA, XRD, FTIR, 29Si NMR, FE-SEM and TEM. Special attention has been devoted to the analysis of changes in the morphological and textural features of the SiO2-sepiolite samples before and after the thermal treatment carried out for removing the organic matter and consolidation of the silica network. This study describes the resulting nanoarchitectures as sepiolite microfibers covalently assembled to silica nanoparticles exhibiting specific surface areas ca. to 350 m2/g, practically without microporous contribution. Preliminary tests regarding the use of the SiO2-sepiolite nanoarchitectures as nanofillers in polymer nanocomposites have been also investigated in order to show one of their potential fields of application. Mechanical properties of epoxy resin nanocomposites have been determined and discussed considering the different nature of the external surface of the intermediate organo-heterostructures and the final inorganic nanoarchitectures.