Carbon dioxide (CO2) geological sequestration is a key pathway for mitigating greenhouse gas emissions, and deep saline aquifers are considered optimal storage sites due to their large potential capacity and lack of economic exploitation value. However, during sequestration, CO2–water–rock interactions significantly influence the mineral composition and mechanical properties of sandstone reservoirs, thereby affecting their injectivity and long-term stability. To explore these effects, Late Paleozoic–Mesozoic sandstones from the southern Hebei region were selected for CO2–water–rock reaction simulation experiments, integrated with pH monitoring, X-ray diffraction (XRD), scanning electron microscopy (SEM), and nanoindentation techniques. The results demonstrate that after reactions, soluble minerals such as calcite and siderite were fully or partially dissolved, feldspar (particularly plagioclase) underwent intensified alteration with the formation of secondary minerals including clays, ankerite, and goethite, while quartz content decreased slightly but remained relatively stable. The pH of the reaction fluid exhibited a dynamic “rise–fall” pattern, reflecting the balance between alkaline ion release during dissolution and consumption during secondary mineral precipitation, with variations in timing and amplitude among lithologies. Pore structures across all sandstone types showed enlarged throats and enhanced connectivity, with honeycomb-like and strip-shaped dissolution pores forming on clay surfaces, and secondary minerals occurring as loose flakes, granules, or flocculent fillings. Microscale elastic modulus and hardness declined markedly by 20.5~41.4% and 10.2~41.2%, respectively, with the most severe degradation observed in Lower Triassic fine sandstones where extensive dissolution of calcite cement reduced intergranular support and produced localized weak zones. These findings suggest that the coupled effects of soluble mineral dissolution (particularly cement minerals such as calcite) leading to framework damage, refilling of pores by mechanically weak secondary minerals (e.g., clays) with inadequate support capacity, and pore structure remodeling with stress concentration induced by dissolution, are the primary mechanisms driving microscale mechanical property degradation and enhanced heterogeneity in sandstones during CO2 geological sequestration, thereby posing potential risks to reservoir mechanical stability during long-term storage.