The performances of In2O3/ZrO2, ZrO2 and In2O3 were evaluated in the synthesis of isobutene from ethanol in one‐step. These catalysts were characterized by XRD, EPR, TPD‐H2O, TPD‐NH3, TPD‐ethanol and pyridine adsorption. The In2O3/ZrO2 catalyst is a promising catalytic system for the synthesis of isobutene from ethanol. The catalytic tests showed that acetone, hydrogen and carbon dioxide are the main co‐products of this synthesis. The In2O3/ZrO2 catalyst can promote the synthesis of isobutene due to the inter‐diffusion process between In2O3 and ZrO2. This phenomenon generates, among others, the Zr insertion and a high concentration of anionic vacancies in the In2O3 lattice. This increases the In2O3/ZrO2 redox properties leading to a high activity of this catalyst for the acetone generation, a key intermediate of the isobutene synthesis. These changes also promote the acid and basic properties of In2O3/ZrO2, which are in charge of the acetaldehyde synthesis, acetone condensation and, finally, dehydration of the intermediates of the isobutene synthesis.