A host−guest system involving ferrocenemethanol (FcOH) and β-cyclodextrin (CD) in both homogeneous (free CD) and heterogeneous conditions (gold-confined CD) is studied by applying an integrated approach that combines energy and structure. Numerical experiments were used to calculate the potential of mean force between the host and guest at different separation distances. The thermodynamic properties of association are obtained by integrating the free-energy profile. In this study, we specially focus on the comparison of the association process between β-CD and FcOH in both isolated and water phases. We establish that the association process is enthalpy driven in all conditions (homogeneous and heterogeneous systems in both isolated and water phases). As a consequence, the driving forces involved in the complexation by β-CD are then essentially due to van der Waals interactions. As concerns the comparison between the isolated and water phases, the simulations have shown that the association constants in vacuum are significantly greater than the corresponding ones in solution. A significant difference appears in the enthalpy between the two conditions. From the analysis of the different energy contributions, we have found that the more favorable free energy in gas comes from the electrostatic contributions. The differences observed between the thermodynamic properties are also interpreted through an atomistic description. The ability of molecular dynamic simulations to enable a better understanding of the role of liquid water and hydrogen bonds on the complexation thermodynamics of β-CD is illustrated in this paper.