An ideal material has yet to be discovered that can completely treat dentin hypersensitivity; however, calcium phosphate precipitation has exhibited potential value for the treatment of dentin hypersensitivity by the occlusion of dentinal tubules. We hypothesized that a novel mesoporous silica biomaterial (nano CaO@mesoporous silica, NCMS) containing nano-sized calcium oxide particles mixed with 30% phosphoric acid can efficiently occlude dentinal tubules and significantly reduce dentin permeability, even with the presence of pulpal pressure. This highly supersaturated Ca2+-and HPO4 2−ion-containing NCMS paste was brushed onto dentin surfaces, and the ions diffused deeply into the dentinal tubules and formed a CaHPO4·2H2O precipitation with a depth of 100 μm. The results of the dentin permeability tests showed that the novel mesoporous material exhibited a significant reduction in dentin permeability (p < 0.05), even under simulated pulpal pressure, as compared with our previously developed material, DP-bioglass, and a commercial desensitizing material, Seal & Protect®.