Hydration free energy (HFE) is a key factor in improving protein-ligand binding free energy (BFE) prediction accuracy. The HFE itself can be calculated using the three-dimensional reference interaction model (3D-RISM); however, the BFE predictions solely evaluated using 3D-RISM are not correlated to the experimental BFE for abundant protein-ligand pairs. In this study, to predict the BFE for multiple sets of protein-ligand pairs, we propose a machine learning approach incorporating the HFEs obtained using 3D-RISM, termed 3D-RISM-AI. In the learning process, structural metrics, intra-/intermolecular energies, and HFEs obtained via 3D-RISM of ∼4000 complexes in the PDBbind database (ver. 2018) were used. The BFEs predicted using 3D-RISM-AI were well correlated to the experimental data (Pearson's correlation coefficient of 0.80 and root-mean-square error of 1.91 kcal/mol). As important factors for the prediction, the difference in the solvent accessible surface area between the bound and unbound structures and the hydration properties of the ligands were detected during the learning process.