A total of 41,825 metal-organic frameworks (MOFs) were computationally screened toward the design of amine-functionalized MOFs for CO2 separation. Both the optimal species and number of amine functional groups were examined for eight MOFs with good performance in terms of CO2 uptake and selectivity. It was revealed that more amine functional groups grafted on the MOFs do not lead to a better CO2 separation capability, and the concept of saturation degree of functional groups was proposed. The ethylene-diamine-functionalized MOF-74 membrane was predicted to possess high CO2 permeation separation capability, which was confirmed by the parallel experimental test of gas permeation.