Mesoporous silica nanoparticles (MSN) are utilized by many applications due to their high surface to volume ratio, tunable pore size, low toxicology, and colloidal stability. These properties make silica nanoparticles good candidates for targeted drug delivery applications. Targeted drug delivery steps include cellular internalization, endosomal escape, and cargo release to the selective tissue. The geometric properties of MSN such as particle size, pore size, and porosity, as well as surface chemistry and resulting surface charge density determine the MSN behavior in these steps. This study examines the influence of particle size, pore size, and porosity of an MSN to its surface zeta potential. We performed both numerical and experimental investigations. The zeta potential of various MSNs at different salt concentrations was calculated by solving the Poisson-Nernst-Planck equation with active surface charge boundary conditions considering surface chemistry. We validated our multi-ion model through experiments. Results indicate that zeta potential exhibits a strong dependence on particle size, pore size, and porosity. By increasing porosity and/or pore size, the absolute average zeta potential decreased up to 25% from the theoretical predictions. Second, zeta potentials of silica particles at different sizes and surface areas were experimentally measured at different salt concentrations. Particles were systematically characterized by measuring particle size using Dynamic Light Scattering (DLS), analyzing chemical properties using Fourier-transform infrared spectroscopy (FTIR), measuring surface area using Brunauer– Emmett–Teller (BET) analysis, and imaging using Scanning Electron Microscopy (SEM). A well-dispersed solution in colloidal stability was obtained by systematically tuning corresponding parameters. The absolute average zeta potential was found to increase with a decrease in particle size, while zeta potential was found to decrease with a decrease in surface area at a constant particle diameter, similar to numerical calculations