One of the major goals of Health 4.0 is to offer personalized care to patients, also through real-time, remote monitoring of their biomedical parameters. In this regard, wearable monitoring systems are crucial to deliver continuous appropriate care. For some biomedical parameters, there are a number of well established systems that offer adequate solutions for real-time, continuous patient monitoring. On the other hand, monitoring skin hydration still remains a challenging task. The continuous monitoring of this physiological parameter is extremely important in several contexts, for example for athletes, sick people, workers in hostile environments or for the elderly. State-of-the-art systems, however, exhibit some limitations, especially related with the possibility of continuous, real-time monitoring. Starting from these considerations, in this work, the feasibility of an innovative time-domain reflectometry (TDR)-based wearable, skin hydration sensing system for real-time, continuous monitoring of skin hydration level was investigated. The applicability of the proposed system was demonstrated, first, through experimental tests on reference substances, then, directly on human skin. The obtained results demonstrate the TDR technique and the proposed system holds unexplored potential for the aforementioned purposes.