Development of spinel bimetallic oxides as low‐cost and high‐efficiency catalysts for catalytic oxidation is highly desired. However, rational design of spinel oxides with controlled structure and components still remains a challenge. A general route for large‐scale preparation of spinel CoFe2O4/C nanocubes transformed from organometal‐encapsulated metal–organic frameworks (MOFs) via exchange–coordination and pyrolysis combined method is reported. Strong confinement effect between organometallics and MOFs realizes reconstruction of crystal phase and composition, but not simple metallic oxides support by Co2+ introduction. Compared with Co3O4‐Fe2O3/C, MOFs‐derived cubic nano‐CoFe2O4/C with higher surface area (115.7 m2 g−1) and favorable surface chemistry exhibits excellent catalytic activity (100% CO conversion at 105 °C) and competitive water‐resisting stability (total conversion at 145 °C for 20 h). Turnover frequency of CoFe2O4/C reaches 4.26 × 10−4 s−1 at 90 °C, two orders of magnitude higher than commercial Co3O4 . Theoretical models show that oxygen vacancies (17.7%) at exposed {112} facet on the carbon interface take superiority in nanocubic spinel phase, which allows reactive species to be strongly adsorbed on nanostructured catalysts' surface and plays key roles in hindering deactivation under moisture rich conditions. The progresses offer a promising way in the development of novel spinel oxides with tailored architecture and properties for vast applications. Confined transformation of organometal‐encapsulated metal–organic frameworks (MOFs) into novel spinel CoFe2O4/C nanocubes is achieved via an innovative methodology combining exchange–coordination and pyrolysis. Strong interaction between the organometallic guest and MOF host leads CoFe2O4/C nanocubes to exhibit superior activity for low temperature oxidation (100% CO conversion at 105 °C) and very competitive water‐resisting stability.