Sequestration of CO2 in deep saline aquifers has attracted positive attention from the scientific community as a mitigatory measure to reduce anthropogenic CO2 in the atmosphere. Caprock layers/zones, which are saturated with brine and CO2 at different degrees of saturation (DOSs), behave differently. Since the risk of CO2 back-migration through different zones in the caprock varies, the focus of this study is on the effects of injected CO2 on the mineralogical and mechanical behavior of caprock with different DOSs due to chemical alteration. A series of reactivity tests were conducted on siltstone samples under different saturation conditions. The experimental results showed that fast dissolution of minerals such as kaolinite and muscovite due to carbonic acid increases the pore volume of caprock. Therefore, flow paths and porosity increase in the fully CO2-brine-saturated zone compared to other zones in the caprock that are not fully saturated with CO2 and brine. In addition, the caprock layer, which is fully saturated with CO2 and brine, has the highest stress corrosion and shear weakening due to mineral dissolution and wetting softening effects, which occur due to surface energy consumption. The next weakest zone in the caprock is the fully brine-saturated siltstone layer due to quartz hydrolysis and wetting softening effects. Therefore, serious attention should be paid to a caprock layer fully saturated with a CO2-brine mixture during sequestration because the risk of CO2 migration via this caprock zone is high, and this affects the permanence and security of injected CO2, especially during periodic CO2 injections and minor seismic events.