Abstract Fractures along interfaces between host rock and wellbore cement have long been identified as potential CO2 leakage pathways from subsurface CO2 storage sites. As a consequence, cement alteration due to exposure to CO2 has been studied extensively to assess wellbore integrity. Previous studies have focused on the changes to either chemical or mechanical properties of cement upon exposure to CO2-enriched brine, but not on the effects of loading conditions. This paper aims to correct this deficit by considering the combined effects of the fracture pathway and changing effective stress on chemical and mechanical degradation at conditions relevant to geologic carbon storage. Flow-through experiments on fractured cores composed of cement and tight sandstone caprock halves were conducted to study the alteration of cement due to exposure to CO2-enriched brine at 3, 7, 9, and 12 MPa effective stress. We characterized relevant reactions via solution chemistry; fracture permeability via changes to differential pressure; mechanical changes via micro-hardness testing, and pore structure changes via x-ray tomography. This study showed that the nature and the rates of the chemical reactions between cement and CO2 were not affected by the effective stress. The differences in the permeability responses of the fractures were attributed to interactions among the geometry of the flow path, the porosity increase of the reacted cement, and the mechanical deformation of reacted asperities. The suite of observed chemical reactions contributed to change in cement mechanical properties. Compared to the unreacted cement, the average hardness of the amorphous silica and depleted layers was decreased while the hardness of the calcite layer was increased. Tomographic imaging showed that preferential flow paths formed in some of the core-flood experiments, which had a significant impact on the permeability response of the fractured samples. We interpreted the observed permeability responses in terms of competition between dissolution of cement phases (leading to enhanced permeability) and mechanical deformation of reacted regions (leading to reduced permeability).