Developing economical and efficient transition-metal oxide catalysts as substitutes of noble metal catalysts for elimination of ketone pollutants is of great concern. However, the reported catalysts still face the challenges of undesirable conversion and CO 2 selectivity at low temperatures, as well as deficient water resistance, which restrict industrial application. In recent years, single-atom catalysts have emerged as hot topics in the field of catalysis due to their exceptional properties, but the relatively high cost and complex preparation methods limit their large-scale application. Herein, α-MnO 2 doped with single-atom Co was synthesized through a simple hydrothermal method. The catalyst with optimal loading (0.1 Co/MnO 2 −H) delivered outstanding performance for the oxidation of acetone, achieving 90% conversion of 100 ppm of acetone at 135 °C with 100% CO 2 yield, far superior to those of Pt/TiO 2 -and MnO 2 -based catalysts. Stable single-atom cobalt on MnO 2 with strong Mn−O−Co interaction, excellent oxygen activation property, low-temperature reducibility, abundant and stable Lewis acid sites, and easier CO 2 desorption contributes to its outstanding acetone oxidation activity at low temperatures. Remarkably, the loading of monatomic Co greatly enhanced the water resistance of Mn-based catalysts. H 2 O-TPD and density functional theory calculations showed that 0.1 Co/MnO 2 −H facilitated water dissociation into hydroxyl groups, which could form a hydrogen-bonded complex with acetone, thus promoting acetone oxidation instead of poisoning. These findings identify a facile and promising approach for preparing stable and high-performance monatomic catalysts for acetone purification as well as other thermocatalytic oxidation reactions, especially with the coexistence of H 2 O impurity.