The long-term interaction of CO2-charged fluids with low permeability cap rocks is important for seal integrity assessment. To address this potential risk, we studied long-term geomechanical changes in a reservoir seal due to fluid-rock interactions with CO2-charged fluids, focusing on a natural CO2 analogue near Green River, Utah, USA. The observed chemo-mechanical changes are on the millimeter scale, which required small-scale petrophysical, mineralogical, and micromechanical analyses. Results showed that over the 7 cm thick reaction front, the low permeability cap rock underwent mechanical weakening, as indicated by indentation tests. This weakening is inferred to be due to dissolution of dolomite and hematite, with the former leading to porosity decrease, as shown by small-angle neutron scattering, while the latter likely led to loss of electrostatic forces between the clay particles. This resulted in loss of cohesion, compaction, and formation of bedding-parallel fractures. Microfracturing occurred in situ, as evidenced by fractures infilled with pyrite and gypsum. This study demonstrates that mechanical weakening of cap rocks might occur, but only over time scales of ~100,000 yr and over small distances. Considering the thickness of cap rocks above CO2 storage reservoirs, we do not anticipate a considerable threat of losing containment integrity over time scales of hundreds to thousands of years as a result of these small-scale fluid-rock interactions.