Concerns about the environmental impacts associated with large-scale CO2 sequestration remain among the public despite the global carbon-neutral demands and successful performances in CO2 storage research, pilot, and commercial projects. Besides the common risks from CO2 leakages, the hazard of reservoir pore pressure increment induced by hundreds of millions of tonnes of CO2 injections is usually overlooked. Significant pore pressure increases within the storage zone may force the connate fluids to be uplifted into freshwater aquifers through potential conduits through the caprock, which poses threats to the underground source of drinking water (USDW). Therefore, a method to quantitatively trace and minimize the susceptible areas around the large-scale CO2 storage location is essential to reduce and control the potential hazards. The United States environmental protection law requires the operators to delineate an Area of Review (AoR), and methods of AoR delineation have been formulated by U.S. Environmental Protection Agency (EPA). This paper established the AoR delineation process from an ongoing San Juan Basin CarbonSAFE Phase III: Ensuring Safe Subsurface Storage of CO2 in Saline Reservoirs project funded by the U.S. Department of Energy (DOE). This study constructed a flow model with comprehensive geologic features identified by characterization efforts. A multi-phase compositional simulator is used to design and implement cases targeting sequestering over 50 million metric tonnes of CO2 over 30 years while various critical storage trapping mechanisms are considered. In the end, the potential impacts on the USDW resulting from the CO2 injection activities were evaluated through AoR delineations. Our preliminary results indicate that properly identifying the depth of the lowermost USDW and the depth of injection zones is essential to delineate the AoR accurately. The density of the formation saline is also highly influential to the size of the AoR. Compared with the risk of CO2 plume migration, pore pressure build-up in the storage reservoir is more likely to jeopardize the USDW during large-scale gas sequestrations. Further, the largest AoR appeared at the end of the injection activity. Therefore, to guarantee the safety of USDW from injection activities, stringent monitoring efforts are particularly required in this region during CO2 injection and post-injection care. Therefore, controlling the size of AoR will increase the overall storage capacity while complying with the environmental protection law. This work employed realistic reservoir characterization data including 3D seismicity, well logs, core analysis, and fluid sampling. As the worldwide commercial CO2 geologic storage projects aim for soaring storage capacity goals, this work underscored an indispensable but sometimes discounted aspect of environmental impacts associated with large-scale CCUS projects. The hazard from connate fluid contamination is as noteworthy as that of CO2 leakage to environmental safety.