<p>Understanding the interplay between chemical reactions and mechanical degradation in rocks is essential for ensuring the sustainability and resilience of geo-structures, as well as advancing subsurface technologies, such as carbon storage, geothermal energy, and enhanced oil recovery. The chemical reactivity of mineral constituents in shale, particularly under CO₂-rich brine conditions, drives complex transformations that alter the rock matrix and its microstructure. These changes, driven by processes, such as mineral dissolution, secondary mineral precipitation, stress corrosion cracking, and mineral oxidation, have significant implications for a wide range of critical applications. This study explores the chemo-mechanical and microstructural evolution of Marcellus shale under high-pressure and high-temperature CO₂-rich brine conditions, focusing on reaction durations of 14 and 28&#xa0;days. Using advanced techniques, such as nano-indentation, micro-CT imaging, and EDS-based chemical mapping, the findings highlight significant processes, including carbonate dissolution, pyrite oxidation, and stress corrosion cracking in quartz. Stress corrosion cracking in quartz was identified as a key mechanism for micro-crack generation, with crack density increasing progressively over time. Pyrite oxidation, primarily near the reacted surface, released H⁺ ions that initiated deeper chemical reactions, promoting carbonate dissolution and the precipitation of secondary iron oxides. Additionally, distinct spatial patterns of mineral dissolution, precipitation, and mechanical weakening were observed. Clay precipitation occurred near the surface due to localized silicate dissolution, whereas calcium carbonate formed in deeper pores, influenced by pore-size-controlled solubility (PSC) and fluid transport dynamics. The interplay of these processes led to significant weakening of the rock, altering its microstructure and mechanical properties.</p>