Major concerns of carbon dioxide (CO2) sequestration in subsurface formations are knowledge of the well injectivity and gas storage capacity of the formation, the CO2 pressure and saturation plume extensions during and after injection, and the risks associated with CO2 leakage and fault reactivation. Saline reservoirs are considered as one of the target formations for CO2 sequestration through structural, residual, dissolution, and mineral trapping mechanisms. The boundary condition of the saline reservoir dictates the pressure and saturation plume extension of the injected supercritical CO2 that could expand over large distances. This can lead to sources of risk, e.g., leakage and/or fault reactivation due to presence of wells, thief zones, and geological discontinuities. Therefore, there is a critical need to develop a model that describes how risk-related performance metrics (i.e., the CO2 saturation plume size, the pressure differential plume area, and the pressure differential at specific locations) vary as a function of the size of injection, time following injection, injection operations, and geologic environment. In this study, a systematic reservoir modeling studies of anthropogenic CO2 sequestration in Citronelle dome, Alabama, was performed where all relevant scenarios and conditions to address the questions of the saturation and pressure plume size in the area of review (AoR) and post-injection site care (PISC) are considered. The objective for this study was firstly to systematically simulate CO2 sequestration, i.e., saturation dynamics, and pressure behavior over a range of operational and geological conditions and to derive conclusions about the factors influencing saturation and pressure plume size, post-injection behavior, and the risk associated with them, by developing third-generation reduced order models (ROMs) for reservoir behavior. Finally, to assess the uncertainty associated with our studies, Latin Hypercube Sampling (LHS) together with an experimental design technique, i.e., Plackett−Burman design, was used. Application of Pareto charts and respond surfaces enabled us to determine the most important parameters impacting saturation and pressure plume sizes and to quantify the auto- and cross-correlation among different parameters in both history-matched and upscaled models.