An understanding of polymorphic protein crystal growth has potential applications in areas such as drug delivery, storage, and purification. We examined polymorphs of glucose isomerase to characterize the properties of polymorphic crystal growth and to examine the energetics of protein crystal growth. Transitions of polymorph stability were measured in polyethylene glycol (PEG)/NaCl solutions, and one transition point was singled out for further study. Repulsive second osmotic virial coefficients as well as an increase in solubility of the less stable polymorph beyond the observed polymorph transition suggest that changes in protein hydration upon addition of salt may explain the experimental trends. A combination of atomistic and continuum models was employed to determine the controlling interactions using available crystal structures. Molecular dynamics simulations were interpreted using quasi-chemical theory to determine the level of protein hydration. Water affinity was also examined at 0 M, 1 M and 2 M NaCl. Models and simulations indicate that the level of protein hydration can play a role in crystal polymorphism, while also suggesting the importance of including salts to account accurately for hydration and potential ion binding.