Pyrazinamide and nicotinamide constitute small, rigid molecules, which are of importance in several areas of science, including crystal engineering, chemical synthesis, biochemistry, and pharmacy. This contribution is dedicated to the comprehensive study of experimental charge density distributions and computational analysis of the β form of pyrazinamide and α form of nicotinamide. Static electron density distribution is obtained through application of Hansen and Coppens multipolar formalism, and further analyzed via Baders quantum theory of atoms in molecules (QTAIM). Geometrical and electron density features of both crystals, such as atomic charges, bond critical points, electrostatic potential and experimentally derived intermolecular interactions are described and compared. The presence of the additional nitrogen atom in the aromatic ring of pyrazinamide, when compared to nicotinamide, has, as expected, a major influence on the surrounding atoms, including the amide moiety (0.2 e difference on the carbonyl group carbon atom). This, in consequence, affects the electrostatic potential in this region, and thus the favorable weak interactions of both molecules, what leads to the substantially different crystal packing motifs. These considerations were quantified in terms of computational methods (periodic DFT and PIXEL approaches), resulting in the conclusion of the α form of nicotinamide crystal being more energetically advantageous. Additionally, a proper deconvolution of thermal motion from static charge density provides precise and accurate atomic displacement parameters (ADPs). This allows for estimation of vibrational entropy contribution to the total stabilization of the studied crystal structures by means of Madsen and Larsen approach. It appeared that vibrational entropies obtained by employing ADPs after full multipolar refinement on high-resolution data are in good agreement with the corresponding values derived from ADPs after the transferred aspherical atom model (TAAM) refinement performed on the low-resolution data. This comparison, conducted here for the very first time, opens up the possibility of routine entropy evaluation for various crystal structures using multipole parameter databanks.