High-valent vanadium ions were substituted into the synthetic cryptomelane manganese oxide (K-OMS-2) framework through a simple and low-cost reflux method and investigated for total and preferential catalytic oxidation of carbon monoxide. Substitutional doping of V5+ resulted in materials with modified composition, morphology, thermal stability; and textural, redox, and catalytic properties. The catalytic activity increased with V concentration until an optimum amount (≈10 % V incorporated) was reached, beyond that a structural “crash point” was observed, resulting in a material with low crystallinity, nanosphere morphology, and reduced catalytic activity. An increase in O2 concentration in the feed gas resulted in an increase in conversion over 10% V K-OMS-2. This most active catalyst was deactivated by moisture only at low temperatures and showed better tolerance than undoped K-OMS-2. This catalyst also preferentially oxidized CO to CO2 from 25 °C to 120 °C in large amounts of H2 under dry conditions, without significantly affecting CO conversion. The doped catalyst also showed stable activity and selectivity in long-run experiments. The mobility and lability of surface oxygen, formation of hydroxyl groups, and enhanced surface redox properties promoted by V doping were strongly correlated with the enhancement of catalytic activities of K-OMS-2 nanomaterials.