Polyhedral Oligomeric Silsesquioxanes (POSS) molecules have emerged as promising alternatives to traditional silica nanoparticles and organosilicon molecules due to their ability to attach a variety of substituents to their central siloxane cages. The electronic features of POSS are dependent on the structures of substituents and cages, making them attractive for applications, such as drug nanocarriers, chemosensors, Janus particles, and inorganic–organic nanocomposites. However, the lack of detailed geometric data poses a difficulty in extending POSS studies using the force field method or beyond the quantum mechanical level. To lay a foundation for future experimental and computational studies, we present new theoretical insights into the influence of substituent and cage on the cage geometries (Si–O bond length, pore width, cage volume, etc.) of 16 substituted POSS molecules with various substituents and cages (T7, T8, T10, T12). Our results show that the mean Si–O bond length of the POSS cage can be in the range of 1.619–1.670 Å depending on the substituent and cage. Moreover, we show that the expansion or shrinkage of POSS depends on the types of substituents, rather than the inductive effect of substituents. Our results demonstrate that the conformational stability, dipole moment, and polarizability of POSS depend on the substituents’ size, substituents’ shape, type of functional moieties of substituents, and cage size. In addition, the HOMO-LUMO bandgap of POSS can be tuned by changing the hydrocarbon chain length, number of aromatic rings, and types of functional groups on the substituents. Finally, we report several sets of geometric data that are transferable to the existing parametrization methods of force field models.