Quinazoline Schiff base conjugates have recently attracted considerable attention from the scientific community due to their potential application as anti-cancer drugs and promising multidentate ligands. Unfortunately, reports dealing with the structural characterization of these compounds are incomprehensibly scarce. To contribute and explore the supramolecular features of these perspective compounds, we have prepared and crystalized four quinazoline Schiff base conjugates (SB1= 3-{(E)-[(2,4-dihydroxyphenyl)methylidene]amino}-2-methylquinazolin-4(3H)-one, SB4= 3-{(E)-[(2-chlorophenyl)methylidene]amino}-2-methylquinazolin-4(3H)-one, SB8= 3-{(E)-[(2,3-dihydroxyphenyl)methylidene]amino}-2-methylquinazolin-4(3H)-one, and SB21= 3-[(E)-benzylideneamino]-2-methylquinazolin-4(3H)-one). Single crystals were obtained by recrystallization of the crude products from different solvents, and crystal structures were determined by a single crystal X-ray diffraction. The prepared compounds can be described as Schiff bases composed of 2-methyl-quinazoline-4-one moiety and differently substituted benzene moieties connected by the imine bond. Considering their molecular structure, these compounds are similar, with the most pronounced differences being in the dihedral angle between aromatic systems. In the crystal, compounds with OH groups on the benzene ring (SB1 and SB8) are primarily connected by strong O-H∙∙∙N hydrogen bonds, and unsubstituted (SB21) and Cl-substituted (SB4) compounds via N-H∙∙∙O hydrogen bonds and π∙∙∙π interactions. Thermal analysis results have shown that the highest melting point compound is 2,4-OH-substituted SB1 (226 °C), followed by 2,3-OH-substituted SB8 (201 °C), unsubstituted SB21 (192 °C); the lowest melting was found with Cl-substituted SB4 (159 °C). Additional Hirshfeld surface analysis and intermolecular energy calculations indicate that the electrostatic interactions (hydrogen bonds) have the largest impact on thermal stability, and that the dispersive interactions are important for stability but can be sterically hindered by bulky substituents on aromatic systems.