Hollow periodic mesoporous organosilicas (PMOs) with molecularly homogeneous organic functional groups in the inorganic pore walls are attracting more and more attention due to the high surface areas, tunable pore sizes, low densities, large cavities in the center, permeable thin shells, and versatile organic–inorganic hybrid frameworks, which make them promising in a variety of applications including adsorption, catalysis, drug delivery, and nanotheranostics. Herein, recent advances in the synthesis of hollow PMO nanoparticles with various organic moieties are summarized, and the mechanism and new insights of synthesis approaches, including hard-core templating methods, liquid-interface assembly methods, and the interfacial reassembly and transformation strategy are discussed in-depth. Meanwhile, the design principles, properties, and synthetic strategies for some smart hollow architectures such as multishelled hollow PMOs, yolk–shell structured PMOs, and nonspherical hollow PMOs are discussed. Moreover, the typical applications of hollow PMO nanomaterials as nanoreactors for chemical transformations and nanoplatforms for biomedicine are summarized. Finally, the challenges and prospects for the future development of hollow PMOs are described.