The pharmaceutical cocrystal landscape of ethenzamide has been addressed during the past years with the aim of improving its physicochemical properties, mainly solubility and dissolution rate. Herein four novel ethenzamide cocrystals have been isolated by mechanochemical synthesis and thoroughly characterized by powder and single-crystal X-ray diffraction. Polyphenols have been selected as coformers based on ethenzamide synthon preference as well as their safety profile and antioxidant character. Besides crystallographic analysis, theoretical calculations have been made to evaluate the strength of intermolecular interactions and their role in crystal packing. The results evidence differences in the supramolecular architecture depending on the different polyphenolic isomers used as coformers. Finally, the physicochemical properties of the novel compounds were assessed and compared to those of ethenzamide alone. Although the solubility profile is significantly enhanced, the thermodynamic stability of the novel cocrystals in aqueous medium is restricted to 24 hours. These findings have been correlated with the crystal structure.