In our previous work, we proposed that desolvation and resolvation of the binding sites of proteins can serve as the slowest steps during ligand association and dissociation, respectively, and tested this hypothesis on two protein-ligand systems with known binding kinetics behavior. In the present work, we test this hypothesis on another kinetically-determined protein-ligand system—that of p38α and eight Type II BIRB 796 inhibitor analogs. The kon values among the inhibitor analogs are narrowly distributed (104 ≤ kon ≤ 105 M−1 s−1), suggesting a common rate-determining step, whereas the koff values are widely distributed (10−1 ≤ koff ≤ 10−6 s−1), suggesting a spectrum of rate-determining steps. We calculated the solvation properties of the DFG-out protein conformation using an explicit solvent molecular dynamics simulation and thermodynamic analysis method implemented in WaterMap to predict the enthalpic and entropic costs of water transfer to and from bulk solvent incurred upon association and dissociation of each inhibitor. The results suggest that the rate-determining step for association consists of the transfer of a common set of enthalpically favorable solvating water molecules from the binding site to bulk solvent. The rate-determining step for inhibitor dissociation consists of the transfer of water from bulk solvent to specific binding site positions that are unfavorably solvated in the apo protein, and evacuated during ligand association. Different sets of unfavorable solvation are evacuated by each ligand, and the observed dissociation barriers are qualitatively consistent with the calculated solvation free energies of those sets.