Large-area goafs in a gypsum mine tend to collapse after 10 or more years, but the influencing factors are still unclear, and the effects of multiple factors have not been comprehensively considered. In this study, the failure mechanism and collapse mode of the room-pillar goaf structure were analyzed, and the uniaxial compressive strength tests of the pillars under different conditions were carried out in a laboratory. The influences of water, temperature, and time on the strength of the gypsum rock were considered. These three factors weakened the gypsum rock in different degrees. After 120 days of immersion, water had the greatest effect with a strength-weakening rate of 52.61%. After 20 temperature cycles, changes in temperature had little effect with a strength-weakening rate of 12.60%. After 25 years of aging, the strength-weakening rate of time was 25.13%. These results show how different factors affect the instability and collapse of the goaf structure, which are of great significance for predicting and preventing this from happening.