Metal–organic frameworks (MOFs) are porous crystals with the potential to improve many industrial gas separation processes. Because there is a practically unlimited number of different MOFs, which vary in their pore geometry and chemical composition, it is challenging to find the best MOF for a given application. Here, we applied high-throughput computational methods to rapidly explore thousands of possible MOFs, given a library of starting materials, in the context of Xe/Kr separation. We generated over 137000 structurally diverse hypothetical MOFs from a library of chemical building blocks and screened them for Xe/Kr separation. For each MOF, we calculated geometric properties via Delaunay tessellation and predicted thermodynamic Xe/Kr adsorption behavior via multicomponent grand canonical Monte Carlo simulations. Specifically, we calculated the pore limiting diameter, largest cavity diameter, accessible void volume, as well as xenon and krypton adsorption at 1.0, 5.0 and 10 bar at 273 K. From these data we show that MOFs with pores just large enough to fit a single xenon atom, and having morphologies resembling tubes of uniform width, are ideal for Xe/Kr separation. Finally, we compare our generated MOFs to several known structures (IRMOF-1, HKUST-1, ZIF-8, Pd-MOF, & MOF-505) and conclude that significantly improved materials remain to be synthesized. All crystal structure files are freely available for download and browsing in an online database.