Long-term occlusion of dentin tubules is a challenge due to the relatively easy removal of the inorganic or organic materials used to occlude them by abrasion or erosion of the treated surface. To overcome this problem, the current work aimed to develop a combination nanomaterial system to enable rapid and stable occlusion of dentin tubules. A large-sized calcium-doped silica nanomaterial (187 nm, Ca-DMSN-L) and a small-sized phosphate-doped silica nanomaterial (74 nm, P-DMSN-S) were fabricated and mixed (denoted as L + S; dendritic mesoporous silica nanomaterial denoted as DMSN). Rapid and dense occlusion of dentin tubules was achieved by the topical application of this combination nanomaterial paste to the dentin surface. Fast hydroxyapatite growth was induced by contact with artificial saliva over three repeated 1 min applications. The material occluding the dentin tubules demonstrated strong resistance to acid and abrasion. In comparison, a large-sized phosphate-doped silica nanomaterial (187 nm, P-DMSN-L) was also fabricated and mixed with Ca-DMSN-L to form the L + L material. It also achieved rapid occlusion but showed less resistance to acid and abrasion than the L + S material. The design of using large and small combo material (L + S) has considerable potential for the treatment of dentin hypersensitivity by rapidly causing occlusion of dentin tubules.