During the action of periodic seismic disturbance stress, the rock mass surrounding buried structures will show fatigue damage owing to cyclic loading. To explore the fatigue characteristics and mechanical degradation mechanism of this process, fatigue loading and uniaxial compression tests were carried out on gypsum samples. The conclusions are as follows. With increasing seismic wave amplitude, the stress loading and unloading velocity gradually increases, and the opening of the stress–strain hysteresis loop gradually increases. With increasing seismic wave frequency, the dip angle of hysteresis loops gradually inclines to the -axis (where is stress), and the variation amplitude of hysteresis loops on the -axis (where is strain) decreases gradually. This shows that the greater the amplitude of the seismic wave and the lower the frequency, the greater the damage to rock. Under seismic wave disturbance, with increasing number of disturbances, the original cracks in the sample gradually spread and infiltrate the rock, and secondary cracks gradually develop, indicating that the physical and mechanical properties of the rock gradually deteriorate. There is a strong correlation between the acoustic emission of samples and the stages of the stress–time curve for uniaxial compression. According to the acoustic emission characteristics, the stress–time curve can be divided into four stages: the initial loading stage, the stable crack growth stage, the unstable crack growth to failure stage and the post-peak stage. Compared with the sample before fatigue, the peak strain decreases significantly and the impact energy index increases significantly after fatigue loading. This indicates that some original cracks in the sample are compressed under seismic disturbance, the brittleness of the sample is enhanced and the rockburst tendency is greatly enhanced.