This work deals with the synthesis, crystallization and the polymorphic interpretation of 2-{3-[3-cyano-6-methyl-2-oxo-4-phenylpyridin-1(2H)-yl]propoxy}-4-methyl-6-phenylnicotinonitrile (2). The quantitative analysis of the two polymorphs has been achieved through single crystal X-ray diffraction and Hirshfeld surface analysis. However, differential scanning calorimetry has been performed to determine the thermal stability and density functional theory to interpret the conformation on the propylene linker. Furthermore, the binding affinity of compound 2 was evaluated through a docking study in the COX-2 active site. An in vivo study revealed significant anti-inflammatory activity. Moreover, solubility of both polymorphs was checked in a 50% MeOH–water mixture and phosphate buffer (pH = 7.40).