Replacing a small fraction of cations in a host metal oxide with a different cation (also known as doping) provides a useful strategy for improving the catalytic activity. Here, we report transition metal (Fe, Co, Ni, and Cu)-doped α-MnO2 nanowires synthesized by a one-step hydrothermal method as CO oxidation catalysts. The as-prepared catalysts displayed morphology, crystal structure, and specific surface area similar to those of the pure MnO2 nanowires. A catalytic activity test showed that all doped MnO2 nanowires exhibited much enhanced CO oxidation activity, with the Cu-doped ones being the most active (TOF of 9.1 × 10−3 s−1 at 70 °C). The Cu-doped MnO2 nanowires showed nearly 100% conversion of CO at 100 °C at an hourly gas space velocity of 36,000 mL g−1 h−1, which could last for 50 h without obvious deactivation even in the presence of 2% water vapor. Density functional theory calculations suggested that Cu doping could make the formation of oxygen vacancies in MnO2, which is the rate-determining step for CO oxidation reaction, easier than for Fe-, Co-, and Ni-doped and pristine MnO2. Our work demonstrates a facile and promising strategy for improving the catalytic activity for oxide-based catalysts, which should be applicable for a variety of different chemical reactions.