Smectite may impact the ability of saline aquifer–caprock systems to store CO2 effectively, because of changes in pressure, temperature, and brine concentration induced by the injection of CO2. These changes influence the molar volume of smectite, affecting the short-term structural and stratigraphic trapping, or the dissolution of smectite via the long-term geochemical trapping. This study investigated the d001 value of an interlayer-cation-exchanged smectite, Na-rich SWy-2 (Na-SWy-2), with Ca or Mg (hereafter CaSWy-2 and MgSWy-2). Molar volume experiments used X-ray diffraction and a high-pressure environmental chamber. The extent of smectite dissolution was simulated at experimental conditions by geochemical modeling using a rate equation derived from the transition state theory. CaSWy-2-CaCl2 and MgSWy-2-MgCl2 brine systems showed that increasing the brine concentration from 0.17 M to saturation results in a <18% decrease in d001 values, and increasing the temperature from approximately 33 to 150°C results in <11% decrease. The effect of the interlayer cation shows the d001 values of MgSWy-2 are <0.4 Å higher compared with CaSWy-2. Geochemical modeling shows the extent of dissolution of Na-SWy-2, CaSWy-2, or MgSWy-2 is only <1.1% in acidic conditions. Furthermore, the calculated swelling pressure needed to decrease the H2O sheets in the interlayer, from 3W to 2W, of MgSWy-2 and CaSWy-2 are higher compared with Na-SWy-2. The swelling pressure was approximated from the sum of the osmotic repulsive pressure, the van der Waals attractive pressure, and the hydration pressure. The data suggest that Na-SWy-2, CaSWy-2, and MgSWy-2 may affect saline aquifer–caprock systems to store CO2. The molar volume is affected by changes in pressure, temperature and brine concentration, or swelling pressure from the injection of CO2. An increase in the d001 value of SWy-2 can enhance the sealing capabilities of a caprock by making saline aquifers less porous and less permeable and thus increasing the capability for CO2 storage. In contrast, a decrease in the d001 value can create cracks in a caprock and thus provide conduits for the CO2 to escape. Furthermore, the CO2 injection will cause a decrease in pH, causing smectite to dissolve until it reaches a steady state. However, despite acidic aquifer conditions, SWy-2 has low solubility.