Catalytic oxidation of CO at ambient temperature is an important reaction for many environmental applications. Here, we employed a defect engineering strategy to design an extraordinarily effective Sn-doped Co3O4 nanorods (NRs) catalyst for CO oxidation. Our combined theoretical and experimental data demonstrated that Co2+ in the lattice of Co3O4 were substituted by Sn4+. Based on a variety of characterizations and kinetic studies, this catalyst was found to combine the advantages of the nanorod-like morphology for largely exposing catalytically active Co3+ sites and the promotional effect of Sn dopant for adjusting the textural/redox properties. Additionally, the Sn-substituted Co3O4 NRs can be further activated via heat treatment to achieve low-temperature CO oxidation (T100 ∼ −100 °C) with excellent stability at ambient temperature. This study reveals the importance of Sn-substitution of inactive Co2+ in Co3O4 and provides an ultra-efficient catalyst for CO oxidation, making this robust material one of the most powerful catalysts available up to now.