Adsorption-based heat transfer (AHT) devices are promising alternatives for green energy production and (re)usage; however, they are still limited by the low performance of their benchmark adsorbent materials. Metal–organic frameworks (MOFs) have been ranked among the most promising water adsorbents for this application owing to their potential superior water uptake and moderate hydrophilicity. However, there is still a need to rationalize and understand at the microscopic scale the water adsorption performances of this family of materials to further guide the selection of the next-generation water adsorbents. In this context, a full understanding of the water adsorption mechanism in the most promising MOFs containing coordinated unsaturated sites is still highly challenging. Here, we explore the water adsorption in the mesoporous MOF MIL-100(Fe) containing coordinated unsaturated Fe(III) sites by combining advanced modeling and experimental tools. As a first stage, density functional theory calculations are performed to derive an accurate force field to describe the specific interactions between water and the coordinated unsaturated Fe(III) sites. This force field is further implemented in a grand canonical Monte Carlo scheme to simulate the water adsorption isotherm and enthalpy in the whole range of relative pressures. A validation of the microscopic models and force field parameters is gained from a very good agreement between the experimental and simulated water adsorption data. As a further step, we provide an unprecedented description of the water adsorption microscopic mechanism in this very promising AHT water adsorbent by a careful analysis of the MIL-100(Fe)/H2O interactions at low and intermediate relative pressures as well as the hydrogen bond network and cluster formation at higher relative pressure.