Selective separation of acetylene (C2H2) from carbon dioxide (CO2) remains one of the most challenging industrial processes because of their very similar molecular sizes and physical properties. Considering the low compression limit of C2H2, it is highly desirable to seek porous materials with specific adsorption sites for efficiently discriminating the two gases under ambient conditions. With accurate force fields derived at the ab‐initio level, a large‐scale computational screening was performed in this work to explore the performances of a library of MOFs with open Cu sites for C2H2/CO2 separation. Out of about 800 existing materials retrieved in our database, 3 MOFs were identified that outperform the current adsorbents in terms of C2H2/CO2 selectivity and C2H2 uptake. This prediction paves the ways towards the revisit of such MOFs for this targeted application.