Mesoporous silica spheres with hierarchical hollow/nano structure (MSSH-H/N) have been successfully prepared by a template-guided approach, in which cetyltrimethyl ammonium bromide (CTAB) and polystyrene (PS) emulsion was used as the template of mesopores and hollow core, respectively. A consecutive template mechanism and the formation of the hierarchical hollow/nano structure were proposed on basis of the combined characterizations including transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction patterns (XRD) and nitrogen sorption analysis, which showed that the hierarchical structure is composed of mesoporous hollow SiO2 spheres and discrete mesoporous SiO2 nanoparticles coating on the shell. Ibuprofen (IBU) was chosen as a drug model in delivery and release experiments, and these MSSH-H/N samples exhibited higher drug loading capacity, desired low initial IBU release rate and typical two-phase drug release behavior compared with conventional single-structure (single-shelled) hollow mesoporous silica spheres due to their unique hierarchical hollow/nano structure.