Abstract The rational design of porous materials for CO 2 capture under realistic process conditions is highly desirable. However, trade‐offs exist among a nanopore's capacity, selectivity, adsorption heat, and stability. In this study, a new generation of anion‐pillared metal‐organic frameworks (MOFs) are reported with customizable cages for benchmark CO 2 capture from flue gas. The optimally designed TIFSIX‐Cu‐TPA exhibits a high CO 2 capacity, excellent CO 2 /N 2 selectivity, high thermal stability, and chemical stability in acid solution and acidic atmosphere, as well as modest adsorption heat for facile regeneration. Additionally, the practical separation performance of the synthesized MOFs is demonstrated by breakthrough experiments under various process conditions. A highly selective separation is achieved at 298–348 K with the impressive CO 2 capacity of 2.1–1.4 mmol g −1 . Importantly, the outstanding performance is sustained under high humidity and over ten repeat process cycles. The molecular mechanism of MOF's CO 2 adsorption is further investigated in situ by CO 2 dosed single crystal structure and theoretical calculations, highlighting two separate binding sites for CO 2 in small and large cages featured with high CO 2 selectivity and loading, respectively. The simultaneous adsorption of CO 2 inside these two types of interconnected cages accounts for the high performance of these newly designed anionic pillar‐caged MOFs.