A novel degradation pathway of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) was identified using computational and experimental methods. Density functional theory (DFT) calculations were employed to obtain its unimolecular degradation pathway, and ultrahigh-performance liquid chromatography-high-resolution mass spectrometry, thermogravimetry-Fourier transform infrared spectrometry, thermogravimetry, and differential scanning calorimetric experimental data were used to validate the computationally deduced degradation pathways. Based on the indications from computational and experimental results, the cleavage of the strained fragment from CL-20 was identified instead of NO2 or HONO elimination as in conventional high energy materials. This fragmentation results in the formation of two energetic species, dinitrodihydropyrazine and dinitroformimidamide, which makes CL-20 one of the most powerful energetic materials. This novel degradation pathway of CL-20 will be useful in understanding the decomposition of cage molecules, design of new practical energetic molecules, and development/improvement of thermokinetic codes used for energetic property calculations.