Caprocks play a crucial role in the geological storage of carbon dioxide (CO2) by preventing its escape and thus trapping it into underlying sequestering reservoirs. An evaluation of interaction-induced alteration of the hydromechanical properties of caprocks is essential to better assess the leaking risk and injection-induced rock instability, thus ensuring a long-term viability of geological CO2 storage. We study the changes in minerals, nanopores, elastic velocities, and mechanical responses of a carbonate caprock caused by rock–water/brine–CO2 interaction (CO2 pressure: ≈12 MPa; 50°C). Before the interaction, the total and accessible porosities are 1.6 and 0.6%, respectively, as characterized by the small-angle neutron scattering (SANS) technique. SANS results show that the total porosity of the carbonate caprock increases, apparently because of rock–brine–CO2 interaction, and the increasing rate rises as brine concentration increases (2.2% for 0 M NaCl, 2.6% for 1 M NaCl, and 2.7% for 4 M NaCl). The increase in total porosity is due to the dissolution of calcite, which tends to enlarge accessible pores (by 0.8 to 1.2%) while slightly decreasing the inaccessible pores (by 0.1–0.2%). Under a CO2–acidified water environment, the compressional-wave (P-wave) and shear-wave (S-wave) velocities (5536.7 and 2699.7 m/s) of a core sample containing natural fractures decrease by 8.5 and 8.1%, respectively, whereas both P- and S-wave velocities (6074.1 and 3858.8 m/s) for an intact sample show only ≈0.5% decreases. The interaction also causes more than 50% degradation of the uniaxial compressive strength for the core sample with natural fractures. X-ray microcomputed tomography experiments on three tiny cores (diameter: 1 mm) after 5-day treatment with CO2 (12 MPa) also show that matrix erosion occurs under CO2–acidified water environment but barely occurs without a direct contact with liquid water. Our study suggests that the hydromechanical properties of carbonate caprocks could evolve over the long-term CO2–brine invasion, and it is critical to monitor the CO2–acidified brine interface for a better and long-term evaluation of the caprock integrity.