Organic-inorganic hybrid mesoporous silicas were synthesized via nonionic supramolecular assembly using the co-condensation synthesis technique with the intention of understanding the catalytic domain as well as developing strategies to control the catalytic functionalities at the molecular level. Esterification of free fatty acids in natural oils and fats was used to probe the catalytic activity of the synthesized acid-modified mesoporous catalysts. Application of solid acid catalysts in such reaction systems can possibly simplify the manufacturing process, reducing production costs, as well as eliminate environmental hazards posed by toxic wastes generated in homogeneous catalyzed reactions;The catalytic performance of the functionalized mesoporous silicas was significantly influenced by the median pore diameter of the catalyst, which was tuned using different surfactants. Incorporation of hydrophobic groups into the organic-inorganic acid catalyst enhanced the catalytic conversion of the fatty acids, although the catalytic performance of the resulting catalyst strongly depended on the incorporation technique as well as the size of the hydrophobic organic groups. Decreasing the spatial positioning of the sulfonic acid groups on the pore surface of mesostructured material increased the acid strength of the resulting acid catalyst. This study demonstrated that the catalytic properties of the functionalized mesoporous catalyst were complex and reaction kinetics studies alone could overlook other important factors, such as solution effects, site collaboration, and hydrophobicity of the catalytic domain, that could affect the ultimate performance of the acid solid catalyst. The work demonstrates the potential of intentionally designing the catalytic environment of the organic-inorganic hybrid mesoporous materials at the molecular level.