The method developed previously for studying mechanical properties using quantum chemical calculations was applied to predict the most probable direction of deformation of the piracetam polymorphic Form II under pressure. By the analysis of the pairwise interaction energies between molecules in Form II, this structure was classified as columnar-layered. The shear deformation modeling of the strongly bound fragments in crystal packing predicted the [100] crystallographic direction with a shift energy barrier of 5.2 kcal/mol to be the most probable within the (001) crystallographic plane for Form II deformation. Comparison of Form II before the polymorphic transition and Form V after the crystal structure change confirmed the results of quantum chemical modeling. The analysis of the shift energy profile indicated the characteristic features (a local minimum near the starting point, negative interaction energies between layers during the displacement, and a low shift energy barrier) that can be used to predict a polymorphic transition. The study of the pairwise interaction energies in the piracetam Forms II and V under pressure has revealed that the crystal structure can be changed under pressure in two stages. In the first stage, the polymorphic transition occurs due to the shift of weakly bound layers without changing the columnar-layered type of the crystal structure from the energetic viewpoint. In the second stage, a change in the ratio of the interaction energies between BSM1 and BSM2 results in the transition of the crystal structure type from columnar-layered to columnar without changing the polymorphic form.