A series of isostructural metal–organic frameworks (MOFs), i.e., M-MOF-74 (M=Co 2+ , Mg 2+ , and Zn 2+ ), were prepared and tested as gas-phase catalysts for CO oxidation reactions. Maintenance of the porous structure of M-MOF-74 after degassing at high temperature and exposure to air for 24h enabled a successful gas-phase catalytic study of CO oxidation. Among the M-MOF-74 materials tested, only Co-MOF-74 exhibited catalytic activity because of the unrivalled Lewis acidic character of the coordinatively unsaturated sites (CUSs) in Co-MOF-74. Moreover, the catalytic activity of Co-MOF-74 was superior to that of previously reported MOF-based CO oxidation catalysts in terms of the light-off temperature and specific rate. The high density of CUSs and remarkable porosity of Co-MOF-74 are responsible for the efficient catalytic activity.