We studied the kinetics and mechanism of the dehydration reaction of calcium sulfate dihydrate to hemihydrate under controlled temperature and water vapor partial pressure. From kinetic and reaction rate curves obtained using thermogravimetric analysis (TGA) under isothermal and isobaric conditions, we determined the overall behavior of this dehydration reaction and the effects of the system’s intensive variables on its kinetics. We observed that the reactions take place with an initial induction period that decreases with increasing temperature, followed by a sigmoidal mass loss controlled by both nucleation and growth processes. Characterization of our samples at different points of the reaction allowed us to observe and confirm a surface nucleation process followed by isotropic growth of the nuclei with inward development of the solid product. We then employed the Mampel kinetic model based on the observed experimental results considering the physical nature of the investigated transformation and the real geometry of the particles. From this model, we obtained sets of kinetic parameters for the nucleation and growth processes and their evolution with temperature. We then proposed physicochemical mechanisms for both processes, and they were considered to interpret the kinetic parameters obtained previously. The mechanistic analysis of the system allowed determination of the effects of both temperature and water vapor pressure on the kinetic behavior of the reaction, which corresponds to a novel approach for the dehydration reaction of calcium sulfate dihydrate. The universal kinetic approach used to treat this chemical system in this work can be applied for studying the dehydration of other ionic hydrates.