The transformation of acetone (a byproduct of phenol manufacturing or a bioderived chemical) into mesitylene is a very attractive reaction to prepare renewable fuels and chemicals. This reaction has been studied over both base and acid catalysts, with relevant limitations (side reactions over acid catalysts, oligomerization of isophorones over basic materials, etc.). We propose an alternative strategy to perform this reaction combining acid and basic catalysts either as separate beds or as mechanical mixtures. For this purpose, we first study the reaction over five representative materials (β-zeolite, Al-MCM-41, Mg−Al mixed oxide, MgO, and TiO 2 ). These studies allow determining the rate-limiting steps and identifying the most relevant catalytic properties to enhance the selectivity toward mesitylene, minimizing the deactivation produced by the permanent adsorption and oligomerization as well as side reactions yielding undesired products (β-scissions). Once the combining strategies are studied, we propose using double beds of Al-MCM-41 and TiO 2 as the optimum approach. The observed synergistic effects enhance the mesitylene productivity by more than 57% to the most active catalyst (Al-MCM-41), working at a low temperature (250 °C). This improvement is due to the activity of the base catalyst (TiO 2 ), producing an optimum mixture of mesityl oxide and acetone that contacts with the acid catalyst (Al-MCM-41), where the second condensation and dehydration steps are so fast that the mesitylene production is stable, not being affected by any deactivation process.