Hollow structured mesoporous organosilicas are a research hotspot because of their molecularly organic–inorganic hybrid frameworks, large void spaces, permeable shells, high surface areas, uniform pores, and various applications. However, the previous reported hard-core templating method and liquid-interface assembly approach suffered from complex preparation procedures and poor uniformity for the products. In this work, we demonstrate an in situ dissolution and reassembly method to synthesize monodisperse benzene-bridged hollow mesoporous organosilica/silica nanoparticles (HMOSNs) by sequential addition of tetraethoxysilane (TEOS) and 1,4-bis(triethoxysilyl)benzene in a solution containing a cetyltrimethylammonium bromide (CTAB) surfactant. The formation of HMOSNs is completed in one pot, which is very effective and convenient. The formation mechanism of HMOSNs is ascribed to the fact that TEOS first assembles with CTAB to form mesostructured silica cores, which further dissolve and migrate to the outer layers during the deposition of mesostructured organosilica shells. The prepared benzene-bridged HMOSNs possess uniform diameter (140 nm), large pore volume (2.79 m³/g), high specific surface area (2926 m²/g), and a high doxorubicin-loading content of 16.7%. HMOSNs can deliver doxorubicin (Dox) into human breast cancer cells and reduce their excretion. Thus, the Dox-loaded HMOSNs show a high killing effect against the cancer cells.