Aldol condensations of carbonyl compounds for C-C bond formation are a very important class of reactions in organic synthesis and upgrading of biomass-derived feedstocks. However, the atomic level understanding of reaction mechanisms and structure-activity correlation on widely used transition metal oxide catalysts are limited due to the high degree of structural heterogeneity of catalysts such as commercial TiO₂ powders. Here, we provide a deep understanding of the reaction mechanisms, kinetics, and structure-function relationships for vapor phase acetone aldol condensation through the controlled synthesis of two catalysts with high surface areas and clean, dominant facets, coupled with detailed characterization and kinetic studies that are further assisted by density functional theory (DFT) calculations. Temperature-dependent diffuse reflectance infrared Fourier transform spectroscopy showed the existence of abundant acetone bonded to surface hydroxyl groups (acetone-O_sH) and acetone bonded to Lewis acid sites (acetone-Ti_5c) on the surface of both {101} and {001} facet dominant TiO₂. Intermolecular C-C coupling of theenolate intermediate from acetone-Ti_5c and a vicinal acetone-O_sH is a kinetically relevant step, which is consistent with kinetic and isotopic studies as well as DFT calculations. The {001} facet showed a lower apparent activation energy (or higher activity) than the {101} facet. This is likely caused by the weaker Lewis acid and Brønsted base strengths of the {001} facet which favors the reprotonation-desorption of the coupled intermediate, making the C-C coupling step more exothermic on the {001} facet and resulting in an earlier transition state with a lower activation barrier. It is also possible that the {001} facet has a smoother surface configuration and less steric hindrance during intermolecular C-C bond formation than the {101} facet.