Salt formation is a useful technique for improving the solubility of active pharmaceutical ingredients (APIs). For instance, a nonsteroidal anti-inflammatory drug, diclofenac (DIC), is used in a sodium salt form, and it has been reported to form several hydrate forms. However, the crystal structure of the anhydrous form of diclofenac sodium (DIC-Na) and the structural relationship among the anhydrate and hydrated forms have not yet been revealed. In this study, DIC-Na anhydrate was analyzed using single-crystal X-ray diffraction (XRD). To determine the solid-state dehydration/hydration mechanism of DIC-Na hydrates based on both the present and previously reported crystal structures (4.75-hydrate and 3.5-hydrate), additional experiments including simultaneous powder XRD and differential scanning calorimetry, thermogravimetry, dynamic vapor sorption measurements, and a comparison of the crystal structures were performed. The dehydration of the 4.75-hydrate form was found to occur in two steps. During the first step, only water molecules that were not coordinated to Na+ ions were lost, which led to the formation of the 3.5-hydrate while retaining alternating layered structures. The subsequent dehydration step into the anhydrous phase accompanied a substantial structural reconstruction. This study elucidated the complete landscape of the dehydration/hydration transformation of DIC-Na for the first time through a crystal structure investigation. These findings contribute to understanding the mechanism underlying these dehydration/hydration phenomena and the physicochemical properties of pharmaceutical crystals.