Asphalt pavements on steep slope sections in regions with seasonal freezing are affected by loads and the environment, and the shear resistance and shear fatigue performance attenuation of interlayer adhesive materials become increasingly severe. To study the effect of freeze-thaw cycles on shear fatigue resistance of asphalt pavement interlayer adhesive materials, an asphalt pavement interlayer shear fatigue test device was designed and self-assembled. The ultimate shear strength test of asphalt mixtures was determined using a universal testing machine. The interlayer shear fatigue of asphalt mixtures was tested, and the single factor analysis of shear stress ratio, loading frequency, temperature, and freeze-thaw cycle influence on the interlayer shear fatigue were discussed. The frequency, temperature, freeze-thaw cycles, and practical application parameters were corrected based on a prediction model for shear fatigue life under different shear stress levels, and a prediction model for interlayer shear fatigue life was established. The results show that the shear fatigue failure life of the same adhesive layer specimen decreases with the increase of the stress ratio, and is very sensitive to changes in the stress level. Furthermore, shear fatigue failure life and the stress level are related linearly in double logarithmic coordinates. The interlayer shear fatigue failure life and loading frequency have an exponential change trend. The higher the loading frequency, the greater is the shear fatigue failure between layers of asphalt pavement. The interlayer shear fatigue failure life of the different types of specimens decreases with the increase of the number of freeze-thaw cycles, and has a linear trend. The study results can provide a theoretical basis and technical support for asphalt pavement material selection and structural design on steep slopes in regions with seasonal freezing.