The YBa2Cu3O7 nano/microsized single crystallites with spherical and rod-like morphologies were fabricated hydrothermally. The catalytic performance of the materials was evaluated for methane combustion. It is shown that there was a clear relationship between the alpha-oxygen desorption or initial H-2 consumption rate and catalytic activity. The single-crystalline perovskite-like cuprate catalysts outperformed the polycrystalline counterpart. The good catalytic performance of the hydrothermally derived YBa2Cu3O7 single crystallites is associated with more alpha-oxygen adspecies, better low-temperature reducibility, high-quality single crystallinity, and unique morphology.