Organosilica mesocellular foam (OSMCF), a large-pore material, was successfully fabricated using 1,4-bis(triethoxysilyl)-benzene (BTEB) as a precursor, Pluronic P123 as a template, and 1,3,5-trimethylbenzene (TMB) as a swelling agent. The cell size is tailorable by changing the weight ratio of TMB to P123. Thermogravimetry (TG) analysis revealed that the material had a high thermal stability. The FT-IR spectra and chemical titration suggested that sulfonic acid might be grafted onto the OSMCF by treating with sulfuric acid (98 wt%) and potassium disulfate. After sulfonation, the large-pore acidic catalysts exhibited very high catalytic activities for bulky reactants. The catalysts were evaluated by the hydrolysis of lab-extracted natural fibers or commercial microcrystalline cellulose, and esterification of oleic acid (OA).