In this work we propose an original methodology to predict the isosteric heat of adsorption of polar and non-polar gases adsorbed in different Zeolitic Imidazolate Framework (ZIF) materials, combining molecular simulation results with a quantitative structure–property relationship (QSPR) approach. The main contribution of our study is the development of a series of structural and molecular descriptors that are useful to describe the adsorption capability of adsorbents. A linear relationship is established to correlate the characteristics of gases and ZIF structures with the isosteric heat of adsorption. A simple tool to estimate the hydrophilic/hydrophobic nature of the solids studied is proposed based on the analysis of our simulation results. The promising approach shown in this work would be useful for the selection of organic linkers in the development of new hybrid organic–inorganic materials.