Cryptomelane is an abundant mineral manganese oxide with unique physicochemical features. This work investigates the real capabilities of cryptomelane as an oxidation catalyst. In particular, the preferential CO oxidation (CO-PROX), has been studied as a simple reaction model. When doped with copper, the cryptomelane-based material has revealed a great potential, displaying a comparable activity to the high-performance CuO/CeO2. Despite stability concerns that compromise the primary catalyst reusability, CuO/cryptomelane is particularly robust in the presence of CO2 and H2O, typical components of realistic CO-PROX streams. The CO-PROX reaction mechanism has been assessed by means of isotopic oxygen pulse experiments. Altogether, CuO/CeO2 shows a greater oxygen lability, which facilitates lattice oxygen enrolment in the CO-PROX mechanism. In the case of CuO/cryptomelane, in spite of its lower oxygen mobility, the intrinsic structural water co-assists as active oxygen species involved in CO-PROX. Thus, the presence of moisture in the reaction stream turns out to be beneficial for the stability of the cryptomelane structure, besides aiding into the active oxygen restitution in the catalyst. Overall, this study proves that CuO/cryptomelane is a promising competitor to CuO/CeO2 in CO-PROX technology, whose implementation can bring the CO-PROX technology and H2 purification processes a more sustainable nature.