Large-scale injection of carbon dioxide (CO2) into saline aquifers in sedimentary basins is a promising approach to mitigate global climate change. Songliao Basin, a large continental clastic sedimentary basin in northeastern China, is one of the great potential candidate sites for future CO2 storage in China. In this paper, a three-dimensional CO2 storage model was built to evaluate the CO2 plume evolution and pressure buildup of large-scale CO2 injection into the saline aquifers in the Sanzhao Depression of the Songliao Basin. CO2 was injected into the aquifers through five wells, each with an annual injection rate of 3 Mt over 50 years. The results show that the clastic Yaojia formation at the depth between 900 and 1,600 m with thickness of 150 m might be the favorable layer to store a considerable amount of CO2, and the overlying Nenjiang formation could ensure long-term CO2 containment. The relative low permeability of the upper part of the Yaojia formation seems to play a role of a secondary seal on carbon storage. In current injection scenario, CO2 plume migrates into the formations in the southeast of the depression, which could have potential risk of polluting the freshwater. Therefore, the injection site should stay far away from the southeast of the depression. Moreover, it is very crucial to investigate the permeability distribution of the Yaojia formation because it significantly dominates the CO2 plume migration. After only 6 months of injection, the pressure buildup at each injection site is affected by pressure interference from neighboring sites. The maximum pressure buildup in the formations is 7.8 MPa after 50 years of injection, and it can even reach 10.5 MPa when the injection layers are with lower permeability. The maximum pressure buildup at the bottom of the Nenjiang formation is 6.7 MPa. The gradient of maximum limited formation pressure is about 18 MPa/km, which might cause fractures to open in the formations of the Sanzhao Depression. Continuous injection of CO2 for 50 years may not cause damage to the caprock even when the lower permeability occurred in the upper part of the Yaojia formation. The safety of CO2 storage will be enhanced if the upper part of the storage formation has lower permeability than the lower part.