The comparative study of three calix [4]heterocycles (calix[4]pyrrole, calix [4]furan, and calix[4]thiophene) has been theoretically performed by using high-level density functional theory (DFT) at the MPWB1K/6-311G**//B3LYP/6-311G** level. The effect of different hetero-atoms (nitrogen, oxygen, and sulfur) placed in the heterocycles on the conformational flexibility, thermodynamic stability order, cavity sizes, charge distributions, and binding propensities are examined. The thermodynamic stability differences between the conformers are found to be much greater in calix