Metal–organic frameworks (MOFs) have attracted enormous research interest as precursors/templates to prepare catalytic materials. However, the effect of structural isomerism of MOFs on the catalytic performance has rarely been studied. In this contribution, two topologically different Ce‐benzene tricarboxylate (Ce‐BTC) based on the same ligands and metal centers (viz., “MOF isomers”) are prepared and used as porous supports to load Pt nanoparticles (NPs), which shows distinct differences in porosities and loading behaviors of Pt. Strikingly, an irreversible framework transformation from tetragonal Ce‐BTC to monoclinic isomer is observed during water soaking treatment. The results give clear evidence that Pt/CeO2 derived from tetragonal Ce‐BTC inclines to produce more Pt0 and smaller Pt NPs, which eventually improve the catalytic performance for CO oxidation (T100 = 80 °C). In situ diffuse reflectance infrared Fourier transform spectroscopy analyses demonstrate that the adsorbed CO–Pt0 is the dominant intermediate for CO oxidation, rather than CO–Ptσ+ at the low temperature. Furthermore, MOF isomers based on the same structural units are also found in other Ln‐MOFs, such as Er‐BTC, Eu‐BTC, Y‐BTC, and Ce/Y‐BTC. Overall, this study affords a fundamental understanding of the effect of MOF structural isomers on the catalytic performance of the derived composites. A facile method is devised for synthesizing two structural isomers of Ce‐benzene tricarboxylate (BTC) based on the same ligands and metal centers and then the metal–organic framework (MOF) isomers are used as porous supports to load Pt nanoparticles (NPs), which shows distinct differences in porosities, loading behaviors of Pt, and the catalytic performance in CO oxidation reaction.