The Diels-Alder (DA) reaction between the cage-annulated diene hexacyclo[18.104.22.168(1,6).0(6,13).0(8,12).0(10,14)] hexadeca-2,4-diene-7,16-dione (HHDD) with a cyclohexa-1,3-diene moiety and ethyl propiolate (EP) dienophile was investigated by the DFT method at the B3LYP/6-31+G(d, p) level to elucidate the mechanism and regioselectivity features of the reaction. The geometrical and electronic structures of the caged diene HHDD and EP were studied at B3LYP/6-31+G(d, p) level. In order to identify facial-and regio-selectivity of the DA reaction of HHDD and EP, the frontier molecular orbital (FMO) interactions of the reactants according to the FMO theory, and the molecular electrostatic potential map of HHDD were examined. The potential energy surface (PES) of the related DA reaction was calculated, and optimizations of transition states and of products corresponding to critical points on the PES were performed at the B3LYP/6-31+G(d, p), and their configurations were determined. In addition, the thermodynamic and kinetic parameters of each possible cycloaddition reaction were calculated using the B3LYP/6-31+G(d, p) method to determine whether the reaction occurs under thermodynamic or kinetic control. The thermochemical results showed that the related DA cycloaddition proceeds under kinetic control, and the activation energies of syn cycloadditions are clearly lower than that of anti cycloadditions. The theoretical calculations are in good agreement with experimental results.