Comprehension of the nanomechanical response of crystalline materials requires the understanding of the elastic and plastic deformation mechanisms in terms of the underlying crystal structures. Nanoindentationd ata were combined with structurala nd computational inputs to derive am olecular-level understandingo ft he nanomechanical response in eight prototypical sulfa drug molecular crystals. The magnitude of the modulus, E,w as strongly connected to the non-covalent bond features, that is, the bond strength, the relative orientation with the measured crystal facet and their dispositioni nt he crystal lattice. Additional features derived from the currents tudy are the following. Firstly,r obust synthons well isolatedb yw eak andd ispersive interactions reduce the material stiffness;i nc ontrast, the interweaving of interactions with diverse energetics fortifies the crystal packing. Secondly, mereo bservation of layered structures with orthogonal distribution of strong and weak interactions is ap rerequisite, but inadequate, to attain higher plasticity.T hirdly,i nterlocked molecular arrangements preventl ong-range sliding of molecular planes and, hence, lead to enhanced E values. In ab roader perspective, the observations are remarkable in deriving am olecular basis of the mechanical properties of crystalline solids, which can be exploited through crystal engineering for thep urposeful design of materials with specific properties.