Being well studied, I and II polymorphic structures of aspirin are very suitable for testing a new method to study mechanical properties using quantum chemical calculations. The proposed method consists of two steps: analysis of the pairwise interaction energies between molecules in a structure obtained by the X-ray diffraction study with separation of strongly bound fragments and further quantum chemical modeling of their displacement in relation to each other. Application of this method to aspirin polymorphs I and II showed that they have layered structure and the [001] crystallographic direction within the (100) plane is the most probable for a shear deformation, which correlates well with the data of the nanoindentation method. The energy barriers for the displacement in this direction were calculated as 17.1 and 14.5 kcal/mol for polymorphs I and II, respectively. It was shown that the area of strong repulsion between molecules belonging to the neighboring layers can complicate shear deformation in stable crystal forms I and II of aspirin. A similar study of the latest polymorph IV showed that this structure is not layered but columnar. The easiest shear deformations are possible for the displacement in the [010] crystallographic direction within the (100), (−101), and (001) planes. The low-energy barriers for these displacements (5.4, 8.8, and 9.5 kcal/mol, respectively) and the absence of significant repulsion along all the translation may explain the metastability of this structure. The proposed method is a good tool to predict mechanical properties.