ZnO has been studied intensely for chemical sensors due to its high sensitivity and fast response. Here, we present a simple approach to precisely control oxygen vacancy contents to provide significantly enhanced acetone sensing performance of commercial ZnO nanopowders. A combination of H₂O₂ treatment and thermal annealing produces optimal surface defects with oxygen vacancies on the ZnO nanoparticles (NPs). The highest response of ~27,562 was achieved for 10 ppm acetone in 0.125 M H₂O₂ treated/annealed ZnO NPs at the optimal working temperature of 400 ℃, which is significantly higher than that of reported so far in various acetone sensors based on metal oxide semiconductors (MOSs). Furthermore, first-principles calculations indicate that pre-adsorbed O formed on the surface of H₂O₂ treated ZnO NPs can provide favorable adsorption energy, especially for acetone detection, due to strong bidentate bonding between carbonyl C atom of acetone molecules and pre-adsorbed O on the ZnO surface. Our study demonstrates that controlling surface oxygen vacancies by H₂O₂ treatment and re-annealing at optimal temperature is an effective method to improve the sensing properties of commercial MOS materials.