Herein we demonstrate the preparation and characterization of nanocrystalline ZnO, either pure or promoted with 1–10 wt.% K2O. All catalysts calcined at 400°C were in the nano‐crystallite scale as confirmed by X‐ray powder diffraction analysis in the 22.9–28.0 nm range. According to the CO2‐temperature‐programmed desorption study using thermogravimetric analysis and differential scanning calorimetry techniques, they have a broad spectrum of surface basic sites. Because of the significance of methyl ethyl ketone (MEK) as a next‐generation biofuel candidate with high‐octane, low boiling point, and relatively high vapor pressure. The prepared catalysts were examined during the direct production of MEK via 2‐butanol (2B) dehydrogenation. Among catalysts tested, ZnO promoted with 1% K2O showed a superior catalytic activity towards the conversion of 2B to MEK, that is, 71.7% at a reaction temperature of 275°C. The selectivity for the production of MEK over all catalysts was ≥95% across all catalysts when using N2‐gas as a carrier. The use of airflow in this reaction resulted in a clear loss of selectivity toward MEK production as well as the appearance of undesirable products such as acetone and methanol. All catalytic properties of catalysts, particularly those of moderate strength, were highly correlated with the distribution of surface basic sites. Finally, a reaction mechanism was proposed for the dehydrogenation of 2B, followed by the partial oxidation of MEK.