Theoretical work was performed based on experimental methods described in the literature to simulate and explore feasible routes for the synthesis of energetic octanitrocubane (ONC) and polynitrocubane derivatives. In respective gaseous and liquidous environments, using cubane as the raw material, ONC was successfully synthesized through carboxylation, amination, oxidation and nitration stages, and the related reaction energy barriers were simultaneously acquired. In particular, the polyparametric calibrated gaseous molecular formation enthalpy and the group additivity approach‐estimated molecular density were incorporated using the Kamlet‐Jacobs equation to evaluate the detonation performance of polynitrocubane derivatives. Some high‐energy‐density derivatives were found to have superior characteristics as compared with traditional hexagon (RDX) and octagon (HMX) explosives.