Water–rock interactions can significantly deteriorate the physical and mechanical properties of rocks, and it has been identified as one of the significant factors influencing the stability and safety of structures in rock–soil engineering. In this study, the fracture mechanical properties of sandstone under periodic water–rock interactions and long-term immersion have been studied with central cracked Brazilian disk specimens. The degradation mechanism of water–rock interactions was also studied using a scanning electron microscope (SEM). Finally, the generalized maximum tangential stress and generalized maximum tangential strain criteria were adopted to evaluate the experimental results. The results show that periodic water–rock interactions can remarkably affect the fracture resistance of sandstone. With the increase in the number of cycles, the pure mode I, pure mode II, and mixed mode fracture toughness decreases greatly, however, the values of KIf/KIC and KIIf/KIC decrease slightly. Furthermore, the fracture resistance of sandstone influenced by cyclic wetting–drying is more significant than long-term immersion. Moreover, the fracture criteria, which considers the effect of T-stress, can reproduce the test results very well.