A comparative study of the degradation in a model phosphate buffered saline (PBS) medium of mesoporous mixed silica–zirconia oxides and hybrid organosilica materials is reported, and their thermodynamic and kinetic stability are discussed. Thin film morphology was used to monitor the degradation rates of all these materials for the first time directly in liquid and undersaturated medium. The introduction of zirconium centers in mesoporous materials strongly inhibits degradation and allowed the self-limitation of soluble silica concentration in the immediate environment of the vector. This avoids renucleation of potentially toxic silica small nanoparticles with uncontrolled surface chemistry in the release medium. Chemical modifications (hybridation or zirconia doping) of mesoporous silica allow the fine-tuning of its degradation from hours to days. Methylated thin films are highly stable when the functionalization ratio is high (50%). The hybridation by mercaptopropyl and aminopropyl moieties can be successfully performed without any high thermal treatment, allowing not only slowing down silica dissolution but also opening the possibility to introduce in one-pot other thermally fragile molecules into the vector. Dissolution rates K measured for the first time at different biologically relevant temperatures follows an Arrhenius law: K = KoExp(−Ea/RT). Stabilities of these chemically modified silicas are mainly associated with a strong decrease of the pre-exponential factor K0 of modified silicas. Counterintuitively, activation energies Ea decrease with increasing the hybrid/silica or the zirconia/silica ratios.