The urgent need to find mitigating pathways for limiting world CO2 emissions to net zero by 2050 has led to intense research on CO2 sequestration in deep saline reservoirs. This paper reviews key advancements in lab- and simulation-scale research on petrophysical, geochemical, and mineralogical changes during CO2–brine–rock interactions performed in the last 25 years. It delves into CO2 MPD (mineralization, precipitation, and dissolution) and explores alterations in petrophysical properties during core flooding and in static batch reactors. These properties include changes in wettability, CO2 and brine interfacial tension, diffusion, dispersion, CO2 storage capacity, and CO2 leakage in caprock and sedimentary rocks under reservoir conditions. The injection of supercritical CO2 into deep saline aquifers can lead to unforeseen geochemical and mineralogical changes, possibly jeopardizing the CCS (carbon capture and storage) process. There is a general lack of understanding of the reservoir’s interaction with the CO2 phase at the pore/grain scale. This research addresses the gap in predicting the long-term changes of the CO2–brine–rock interaction using various geochemical reactive transport simulators. Péclet and Damköhler numbers can contribute to a better understanding of geochemical interactions and reactive transport processes. Additionally, the dielectric constant requires further investigation, particularly for pre- and post-CO2–brine–rock interactions. For comprehensive modeling of CO2 storage over various timescales, the geochemical modeling software called the Geochemist’s Workbench was found to outperform others. Wettability alteration is another crucial aspect affecting CO2–brine–rock interactions under varying temperature, pressure, and salinity conditions, which is essential for ensuring long-term CO2 storage security and monitoring. Moreover, dual-energy CT scanning can provide deeper insights into geochemical interactions and their complexities.