The caprock of coal-bearing strata plays a critical role in CO2 geological storage, with the presence of fractures posing a heightened risk of CO2 leakage. The cyclic effects of CO2 injection and in situ stress influence the permeability of caprock fractures. However, the combined impact of CO2 and in situ stress on fracture permeability remains uncertain. This study conducted cyclic seepage experiments under varying amplitude stresses on fractured sandstone samples soaked in ScCO2 for different times (0, 15, 30, and 60 days). The microstructural characteristics of the fractured sandstone surfaces were analyzed using scanning electron microscopy and x-ray diffraction. The experimental results indicated that soaking in ScCO2 reduces sandstone fracture permeability, but the extent of this reduction is nonlinearly related to the soaking time. During the stress cycling process, due to the effect of plastic deformation, the permeability of sandstone fractures decreases with increasing cyclic amplitude and remains relatively constant with decreasing cyclic amplitude. At the same cyclic amplitude, the permeability of sandstone fractures initially increases and then decreases with prolonged soaking time. The impact of ScCO2 and stress cycling on the permeability of sandstone fractures is the result of a series of combined chemical–mechanical effects. The combined effects of chemical dissolution and mechanical degradation significantly influence the permeability of sandstone fractures, and this impact is notably time-dependent. During short-term soaking, geochemically induced changes in the surface structure of fractures cause fluctuations in permeability, while in long-term soaking, the combined chemical–mechanical effects promote a reduction in fracture permeability.