Impacts of fluid–rock geochemical reactions occurring during CO2 injection into underground formations, including CO2 geosequestration, on porosity and single-phase permeability are well documented. However, their impacts on pore structure and multi-phase flow behaviour of porous media and, therefore, on CO2 injectivity and residual trapping potential, are yet unknown. We found that CO2-saturated brine–rock interactions in a carbonate rock led to a decrease in the sweep efficiency of the non-wetting phase (gas) during primary drainage. Furthermore, they led to an increase in the relative permeability of the non-wetting phase, a decrease in the relative permeability of the wetting phase (brine) and a reduction in the residual trapping potential of the non-wetting phase. The impacts of reactions on pore structure shifted the relative permeability cross-point towards more water-wet condition. Finally, calcite dissolution caused a reduction in capillary pressure of the used carbonate rock. For CO2 underground injection applications, such changes in relative permeabilities, residual trapping potential of the non-wetting phase (CO2) and capillary pressure would reduce the CO2 storage capacity and increase the risk of CO2 leakage.