To further understand the structural evolution law of internal and external groups of ε-phase 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (ε-CL-20) molecule skeleton during the heating process, the temperature response law of internal and external groups of ε-CL-20 skeleton was quantitatively compared and analyzed by in-situ Fourier transform infrared spectroscopy (in-situ FT-IR) and differential scanning calorimetry (DSC). Results show that the infrared absorption peak intensity of external groups (—NO₂, C—H) of ε-CL-20 skeleton undergoes three change stages as temperature increases: linear decrease (Z_Ⅰ), accelerated decrease (Z_Ⅱ), and second accelerated decrease (Z_Ⅲ), which correspond to the thermal expansion, thermally induced phase-transition and thermal decomposition process of CL-20 crystal, respectively. The C—N stretching vibration inside the molecular skeleton also undergoes the above-mentioned three stages,but the initial temperature of Z_Ⅱ and Z_Ⅲ regions are significantly higher than that of the external group, indicating that the external groups are more sensitive to temperature than internal groups, whether thermally induced phase-transition or thermal decomposition, while the internal groups of the skeleton respond to temperature only at higher temperature. The temperature response characteristics of C—C stretching vibration inside molecular skeleton are even more complex. As temperature increases, the peak intensity of C—C stretching only undergoes an accelerated reduction process, and a new characteristic peak of C—C stretching vibration is observed, which is closely related to ε-γ phase transition, illustrating that the phase transition process makes the vibration mode of C—C bond inside the molecular skeleton change significantly. After further heating, the relative proportion of the new characteristic peak area is continuously increasing, showing that the change of the vibration mode inside the skeleton is still ongoing until the end of thermal decomposition.