In this study, intermittent creep-fatigue tests were applied on Ni-based Alloy 617 and Alloy 625. Scanning electron microscope (SEM) observation and electron back-scatter diffraction (EBSD) analysis were employed to the evaluation of the degradation of the crystallinity under the creep-fatigue loads. It was found that the initial damage under creep-fatigue load basically appeared as intergranular cracks. In addition, the lifetimes of Alloy 625 samples fluctuated significantly due to the growth of NbC precipitates. The initial damage of these two alloys was dominated by the growth and accumulation of dislocations and vacancies around the interface that consisted of large lattice mismatch. Local atomic diffusion was activated when the summation of the nominal stress and local stress caused by the large lattice mismatch exceeded a critical value. The stress-induced acceleration of the degradation of the crystallinity of the alloys was analyzed by applying the modified Arrhenius equation. Instead of the most popular inversion methods according to the final failure mode, the quantitative description in life prediction was developed based on the dynamic progress for acceleration mechanism of the degradation. It is of importance to perfecting the frontiers of damage mechanics approach.